Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell
 

Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

The Pink Sheet Daily. 2009 Apr 28, S Haley

<!--startindex-->Among the therapies showcased at the recent American Association for Cancer Research meeting in Denver were a growing number aimed at attacking cancer from a new or at least a different angle, through the specialized tumor cells known as cancer stem cells.
Cancer stem cells, the very aggressive cancer cells believed responsible for tumor metastases, are not stem cells in the way embryonic stem cells have captured the scientific imagination, but they are a very small, defined population of cancer cells than can go forth and generate a new tumor. And there's a good chance that if their migration in the body can be stopped, cancers can be made more susceptible to chemotherapy and tumors eliminated entirely, with no nasty surprises years down the road.
When a tumor cell divides it creates one new cancer stem cell, which goes into a resting state, and progeny cells, which become the mass of the tumor. It is these resting cells that are thought to be responsible for not only metastasis but also chemoresistance. They have a very low proliferation rate - so antiproliferatives don't reach them entirely - they overexpress paths that carry drugs out of the cell, and they have more detoxifying enzymes than other tumor cells, Patrick A. Baeuerle, chief scientific officer at Micromet, a company working in the space, explained at the firm's R&D day April 24.
In fact, Baeuerle said, "there is good evidence" that chemotherapy actually enriches the environment for cancer stem cells. When the other cancer cells are eliminated, there are more stem cells to "very rapidly repopulate the tumor."
Micromet harnessing immune system with BiTE antibodies
Micromet's BiTE antibody MT110 can successfully direct the immune system's T-cells to eliminate human colorectal cancer stem cells in cell culture and in animal models, the company reported at AACR.
At the R&D day, Baeuerle explained the significance of MT110's efficacy "in a dish and in a mouse." Eradicating 100 percent of the cells is important because as few as 100 stem cells left in the body after treatment can give rise to a new tumor later on, he said. In both the Petri dish and mouse model, MT100 yielded complete inhibition - meaning there was no further colonization in culture and no tumor growth in the animals.
Using its bispecific T-cell engager (BiTE) technology, the biotech engineered an antibody able to tether resting T-cells to tumor cells, then deliver a cytotoxic payload. MT110 is specific for epithelial cell adhesion molecule (Ep-CAM), a target antigen highly expressed on the surface of cancer stem cells from a variety of tumor types. The biologic is in a Phase I dose-escalating clinical trial in patients with lung or gastrointestinal cancer.
Geron going after telomerase inhibition with imetelstat
Another company working in the cancer stem cell space, Geron, gave five presentations at AACR involving its telomerase inhibitor imetelstat (GRN 163L). It is being studied against cancer stem cells from non-small cell lung, breast, pancreatic, prostate and pediatric neural tumors. Imetelstat is a short chain oligonucleotide with a high affinity and specificity to the telomerase site, thus inhibiting enzyme activity.
Imetelstat currently is in six clinical dose-ranging/safety trials. The drug is being tried in combination with standard of care carboplatin and paclitaxel in a Phase I/II trial testing it against non-small cell lung cancer.
Preclinical data shared at AACR showed that continued treatment of NSCLC cell lines with imetelstat induced progressive decreases in telomere length, resulting in cell death. Treatment over several months resulted in "a dramatic decrease" in colonies in culture, investigators said. In addition, they noted "marked" changes in the number of genes associated with stem cell proliferation. Together, the results mean imetelstat will have to be administered over a sustained period and that the cancer stem cells responsible for NSCLC proliferation were indeed targeted by the drug, investigators said.
Geron also presented preclinical data against four human prostate cancer cell lines, in which tumors express high levels of telomerase activity, suggesting clinical trials could produce a positive result in that cancer. Telomerase is absent or expressed occasionally and only at low levels in normal adult tissue. In another presentation of research, in pediatric neural tumors, including neuroblastoma, preclinical data show telomerase is only active in the tumor's stem cells and that treatment resulted in inhibition of telomerase, loss of replicative potential, and cell aging. In addition, cells pre-treated with imetelstat appeared more susceptible to radiation.
Geron, in Menlo Park, Calif., is best known as the stalwart company that continued its research with human embryonic stem cells during the Bush administration ban on federally funded investigations in that area, a complication that hindered the ability of university researchers to participate in studies of Geron candidates.
In January, FDA lifted a clinical hold on Geron's regenerative stem cell therapy OPC1, allowing Geron to proceed with human trials in spinal cord injury.
Biotechs not alone: big pharma pursuing cancer stem cells, too
Big pharmas also have been edging into the cancer stem cell space, as the increasing emphasis on oncology portfolios increases demand for novel approaches.
In 2007 Sanofi-Aventis formed a collaboration with Chinese researchers at the Tianjin Institute of Hematology and Blood Diseases Hospital. That same year, GlaxoSmithKline and Redwood City, Calif.-based OncoMed formed a back-end loaded relationship worth up to $1.4 billion for the biotech if the cancer stem cell bet pays off. Then in 2008, Roche paid $190 million in cash to take over Canadian antibody company Arius Research and gain control of its cancer stem cell program.
That leaves plenty of big pharma firms focused on oncology that could be interested in the programs from Micromet and Geron.

Researchers target telomeres to attack tumors

5. May 2009 19:09Hoping to develop more effective long-term attacks on cancer, researchers at the Indiana University School of Medicine are conducting the first human tests of a breast cancer drug regimen that includes a compound meant to force cancer cells to grow old and die.

The early stage clinical tests are an attempt to block a mechanism cancer cells use to avoid the aging process that affects most normal cells. If successful, the new therapy could enhance the effects of other cancer treatments.
"This is really a completely different way of trying to tackle the problem that hasn't been tested in the clinic before," said Kathy Miller, M.D., associate professor of medicine and Sheila D. Ward Scholar at the IU School of Medicine and medical oncologist at the Indiana University Melvin and Bren Simon Cancer Center.
The clinical test is a good example of how positive results in basic science experiments can push a promising compound from the laboratory to the bedside - a process known as "translational research."
The new approach is based on research into telomeres, the caps that protect the ends of the 46 chromosomes in each cell that contain our genetic information. The telomeres, which some compare to the tips of shoelaces, help prevent genomic instability. Each time a cell divides, the telomeres shorten. When they become too short, losing their protective ability, it's a signal to the cell to die, or to go into a state of permanently arrested growth called senescence.
Telomeres in cancer cells generally are shorter than those in normal cells. That offers a tempting target, except that cancer cells know a trick. Cancer cells produce an enzyme called telomerase, which provides maintenance services on the telomeres, preventing them from reaching the critically short stage that would set off the cell death signal.
So, researchers have figured, if you could block cancer cells from producing telomerase, you could make them easier to kill. But how to do that? Several approaches seemed possible, including one that Brittney-Shea Herbert, Ph.D., then a post-doctoral researcher, was working on 10 years ago at the University of Texas Southwest in Dallas. Her approach: Find a special type of chemical compound, called an oligonucleotide, that would block access to telomerase and prevent it from doing its job. She began working with a new compound, with the chemical name GRN163L, that had been developed by Geron Corp. of Menlo Park, Calif.
Dr. Herbert has continued to work with GRN163L - now called imetelstat sodium - in the laboratory since coming in 2003 to the IU School of Medicine, where she is an assistant professor of medical and molecular genetics. She has published work showing that imetelstat disrupts telomere maintenance, in the process suppressing both tumor growth and metastasis - the appearance of tumors in other tissues. Another study found that telomere damage in breast cancer cells treated with the compound caused the cells to be more susceptible to radiation treatment. Furthermore, she has shown that imetelstat can restore the sensitivity of Herceptin-resistant breast cancer cell lines in the laboratory.
"What's interesting about GRN163L is that it can get into almost any cancer cell type, including drug resistant cancer cells. That's been a problem: A lot of agents cannot be taken up into drug resistant cells. This telomerase inhibitor can be taken up in any cell type - you can target those cells. So that's why we hope this will be great for reducing recurrence and metastasis," said Dr. Herbert.
Such results have made imetelstat an attractive compound to test in conjunction with other anti-cancer drugs, which is what brought Drs. Miller and Herbert together. They are testing imetelstat with the drugs Taxol and Avastin, initially to determine the appropriate dose of imetelstat, test whether the three drugs are safe to give in combination, and to determine whether there are side effects that must be dealt with.
Assuming the first phase goes well a second phase of testing will begin more formal evaluation of how well the combination therapy works.
Dr. Miller's research has shown that Taxol and Avastin are more effective in combination than Taxol alone, shrinking tumors in about twice as many women and providing such benefits more than twice as long. The therapy doesn't cure metastatic disease, though. Eventually the tumors become resistant to the drugs and other treatments are necessary.
If, as expected, imetelstat doesn't raise side effects issues, and "if it makes the cells more sensitive to the effects of the Taxol and Avastin, and allows the benefits of that therapy to continue for a much longer period of time, that would be a big benefit for those ladies with metastatic disease. It would also then give us the support for looking at this agent even earlier in the course of disease," said Dr. Miller.
Dr. Herbert's research indicated that imetelstat can reduce metastatic spread of cancer, though it's not yet clear what the mechanism is. But, as Dr. Miller points out, for patients that will be a distinction with little difference.
"Whether it actually prevents the cells from spreading or they spread but can't grow to make clinically apparent tumors we don't know, but I can tell you my patients don't care," she said.
http://www.iupui.edu


Hum Pathol.. [Epub ahead of print]
Reduction of CD44(+)/CD24(-) breast cancer cells by conventional cytotoxic chemotherapy.

Aulmann S, Waldburger N, Penzel R, Andrulis M, Schirmacher P, Sinn HP.
Institute of Pathology, Heidelberg University, 69120 Heidelberg, Germany.
Breast cancer cells with the CD44(+)/CD24(-) phenotype have been associated with stem cell properties. To analyze effects of cytotoxic chemotherapy on these cells, we examined a series of 50 breast carcinomas before and after neoadjuvant chemotherapy with epirubicin/cyclophosphamide using double immunofluorescence. Before treatment, an average of 4.4% of the tumor cells displayed a CD44(+)/CD24(-) phenotype. However, after chemotherapy, the frequency of CD44(+)/CD24(-) cells dropped to 2% (P = .008). To test this unexpected finding, we analyzed a second collective of 16 patients that preoperatively had received either 4 cycles of doxorubicin/pemetrexed, followed by 4 cycles of docetaxel or 4 cycles of doxorubicin/cyclophosphamide, followed by 4 cycles of docetaxel with similar results (8.7% CD44(+)/CD24(-) cells on average before and 1.1% after chemotherapy). In addition, no association was observed between the frequency of CD44(+)/CD24(-) cells and the response to chemotherapy or patient survival. However, patients with tumors containing high numbers of CD44(+)/CD24(-) cells more frequently developed bone metastases in the course of disease. In conclusion, our findings challenge the proposed role of CD44(+)/CD24(-) cells as cancer stem cells in tumor resistance to chemotherapy as they apparently are not selected by conventional cytotoxic agents.

PMID: 20004947 [PubMed - as supplied by publisher]





Int J Cancer. 2009 Nov 11. [Epub ahead of print]
The effects of telomerase inhibition on Prostate tumor-initiating cells.

Marian CO, Wright WE, Shay JW.
University of Texas Southwestern Medical Center, Department of Cell Biology, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9039.
Prostate cancer is the most lethal malignancy in men and the patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies. (c) 2009 UICC.

PMID: 19908230 [PubMed - as supplied by publisher]


Experimental drug (Imetalstat) shows promise against brain, prostate cancers
http://news.xinhuanet.com/english/20...t_12749320.htm


<dl class="AbstractPlusReport"><dt class="head">1: Eur J Gynaecol Oncol. 2001;22(5):347-9.<script language="JavaScript1.2"><!-- var Menu11766737 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=11766737&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=11766737&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1176 6737&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Herbal complex suppresses telomerase activity in chemo-endocrine resistant cancer cell lines.

<!--AuthorList-->Lian Z, Fujimoto J, Yokoyama Y, Niwa K, Tamaya T.
Department of Obstetrics and Gynecology, Gifu University School of Medicine, Gifu City, Japan.
A herbal complex consisting of Hoelen, Angelicae radix, Scutellariae radix and Glycyrrhizae radix suppressed cell viability and telomerase activity in hormone-refractory and chemo-resistant cancer cell lines, namely poorly differentiated uterine endometrial cancer cell line AN3 CA, adriamycin-resistant breast cancer cell line MCF7/ADR and cisplatin-resistant ovarian cancer cell line A2780. Furthermore, the herbal complex suppressed the expression of the full length of human telomerase reverse transcriptase (hTERT), which is related to telomerase activity. This indicates that the herbal complex can suppress the tumor growth of chemoendocrine resistant cancers, at least in part via suppression of telomerase activity associated with down-regulated hTERT.
PMID: 11766737</dd><dt>
</dt><dt>Surprise!
</dt><dt>Herbal mix has patent: http://www.freepatentsonline.com/7527812.html</dt></dl>
What? Is this bad? Excercise activates and reduces shortening of Telomerase? http://www.fightaging.org/archives/2...-telomeres.php




Blocking inflammation receptor kills breast cancer stem cells, study finds
1/4/2010
http://www.physorg.com/news181851567.html

Scientists at the University of Michigan Comprehensive Cancer Center have uncovered an important link between inflammation and breast cancer stem cells that suggests a new way to target cells that are resistant to current treatments.

More information: Journal of Clinical Investigation, Vol. 120, No. 2, February 2010; doi:10.1172/JCI39397



Other available Interleukin-8 inhibitors:

Thymiquone from Nigella Sativa or black cumin
(used in Indian spice Charnushka)

Wikipedia
Thymoquinone is a phytochemical compound found in the plant Nigella sativa. It has antioxidant effects and has been shown to protect against heart, liver and kidney damage in animal studies, as well as having possible anti-cancer effects.<sup id="cite_ref-0" class="reference">[1]</sup><sup id="cite_ref-1" class="reference">[2]</sup><sup id="cite_ref-2" class="reference">[3]</sup><sup id="cite_ref-3" class="reference">[4]</sup><sup id="cite_ref-4" class="reference">[5]</sup><sup id="cite_ref-5" class="reference">[6]</sup><sup id="cite_ref-6" class="reference">[7]</sup> It also has analgesic<sup id="cite_ref-7" class="reference">[8]</sup> and anticonvulsant effects in animal models.<sup id="cite_ref-8" class="reference">[9]</sup> It is an angiogenesis inhibitor.

Sloan Kettering description and links
http://www.mskcc.org/mskcc/html/69141.cfm

Nigella sativa web

More background and Oil and capsules available here:
http://www.kitchendoctor.com/herbs/black_cumin.php



Herbal extract inhibits pancreatic cancer development
LINK ABSTRACT
April 20th, 2009
Dr. Arafat said that Nigella sativa seeds and oil, used in traditional medicine by many Middle Eastern and Asian countries, helps treat a broad array of diseases, including some immune and inflammatory disorders.
Previous studies have also shown it to have anti-cancer effects on prostate and colon cancers.
Based upon their previously published findings that thymoquinone inhibits histone deacetylases (HDACs), Dr. Arafat and her colleagues compared the anti-inflammatory properties of thymoquinone and trichostatin A, an HDAC inhibitor that has previously shown to ameliorate inflammation-associated cancers.
The researchers used pancreatic ductal adenocarcinoma (PDA) cells, some of which were pretreated with the cytokine TNF-alpha to induce inflammation.
Thymoquinone almost completely abolished the expression of several inflammatory cytokines, including TNF-alpha, interleukin-1beta, interleukin-8, Cox-2 and MCP-1, an effect that was more superior to the effect of trichostatin A.
The herb also inhibited the activation and synthesis of NF-kappaB, a transcription factor that has been implicated in inflammation-associated cancer.
Activation of NF-kappaB has been observed in pancreatic cancer and may be a factor in pancreatic cancer’s resistance to chemotherapeutic agents.
When animal models of pancreatic cancer were treated with thymoquinone, 67 percent of the tumours were significantly shrunken, and the levels of proinflammatory cytokines in the tumours were significantly reduced.

Telomerase, inflammation/IL-8....let's keep adding to the list of cancer stem cell strategies.


Hmmm..
However it does it, Milk thistle seems to reduce a proposed cancer stem cell marker:


Am J Transl Res. 2009 Jan 1;1(1):80-6.
Silibinin suppresses CD44 expression in prostate cancer cells.

Handorean AM, Yang K, Robbins EW, Flaig TW, Iczkowski KA.
Prostate cancer (PCa), like most human cancers, features dysregulated CD44 expression. Expression of CD44 standard (CD44s), present in benign epithelium, is lost in PCa while pro-invasive splice variant isoform CD44v7-10 is overexpressed. The role of CD44 in silibinin's anti-growth effects was uncertain. To assess silibinin's effects on CD44 promoter activity, PC-3M PCa cells were transfected with luciferase-CD44 promoter construct 24 h prior to 25-200 muM silibinin treatment for 48 h. Also, cells' expression of CD44 RNA (by qRT-PCR) and protein (Western blot analysis) was studied. Silibinin was further tested preoperatively on a pilot cohort of 6 men with PCa compared with 7 matched placebo-treated men, with immunostaining for CD44v7-10 in their prostates. In PC-3M cells, silibinin dose-dependently inhibited CD44 promoter activity up to 87%, caused a 90% inhibition of total CD44 and 70% decrease in CD44v7-10 RNA, and at the protein level, decreased total CD44 at 100-200 muM dose and decreased CD44v7-10 after 3 days. Silibinin decreased adhesion to hyaluronan and fibronectin. Silibinin at 100-200 muM inhibited Egr-1, a regulator of CD44 promoter activity. Men treated with silibinin did not differ in tissue CD44v7-10 expression. In conclusion, CD44 inhibition is one mechanism by which silibinin reduces PCa tumorigenicity.

PMID: 19966941 [PubMed - in process]




Proc Natl Acad Sci U S A. 2010 Feb 3. [Epub ahead of print]
Selective targeting of radiation-resistant tumor-initiating cells.

Zhang M, Atkinson RL, Rosen JM.
Department of Molecular and Cellular Biology and Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030-3498.
Tumor-initiating cells (TICs) have been shown both experimentally and clinically to be resistant to radiation and chemotherapy, potentially resulting in residual disease that can lead to recurrence. In this study, we demonstrate that TICs isolated from p53 null mouse mammary tumors repair DNA damage following in vivo ionizing radiation more efficiently than the bulk of the tumor cells. Down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed both in fluorescence activated cell sorting (FACS)-isolated TICs as compared to non-TICs and in TIC-enriched mammospheres as compared to primary tumor cells depleted of TICs. This effect was accompanied by increased Akt signaling, as well as by the direct activation of the canonical Wnt/beta-catenin signaling pathway specifically within the TIC subpopulation by phosphorylation of beta-catenin on serine 552. Using limiting dilution transplantation performed on p53 null tumor cells transduced with Wnt reporter lentivirus, we demonstrated that FACS sorting of cells expressing TOP-eGFP resulted in a marked enrichment for TICs. Furthermore, FACS analysis demonstrated that cells with active Wnt signaling overlapped with the TIC subpopulation characterized previously using cell surface markers. Finally, pharmacological inhibition of the Akt pathway in both mammospheres and syngeneic mice bearing tumors was shown to inhibit canonical Wnt signaling as well as the repair of DNA damage selectively in TICs, sensitizing them to ionizing radiation treatment. Thus, these results suggest that pretreatment with Akt inhibitors before ionizing radiation treatment may be of potential therapeutic benefit to patients.

PMID: 20133717 [PubMed - as supplied by publisher]

Ah....
 

forgot about reovirus. Here are some trials:
http://www.oncolyticsbiotech.com/clinical.html

Oncolytics Biotech is directing a broad clinical trial program with the objective of developing REOLYSIN® as a human cancer therapeutic. The current clinical program includes human trials using REOLYSIN® alone and in combination with chemotherapy or immune modulation, and delivered via local administration and/or intravenous administration. The Company's first pivotal trial will be a Phase III randomized clinical trial examining the intravenous administration of REOLYSIN® in combination with paclitaxel and carboplatin in patients with platinum-failed head and neck cancers.
Clinical Trial Chart

Click on clinical trial for more detailed information
<table bgcolor="#c4bcd3" border="0" cellpadding="4" cellspacing="1" width="700"><tbody><tr> <td class="headertext" bgcolor="#d9d5e1" width="106">Trial Name</td> <td class="headertext" bgcolor="#d9d5e1" width="186">Delivery Method</td> <td class="headertext" bgcolor="#d9d5e1" width="206">Trial Program
and Cancer Indication</td> <td class="headertext" bgcolor="#d9d5e1" width="68">Location</td> <td class="headertext" bgcolor="#d9d5e1" width="88">Status</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 016</td> <!-- added Sept 09 2008 --> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with paclitaxel and carboplatin</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase II non-small cell lung cancer</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 015</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with paclitaxel and carboplatin</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase II head and neck</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 014</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase II sarcomas</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 013</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration monotherapy (sponsored by University of Leeds)</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Translational metastatic colorectal </td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">NCI Trial</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration monotherapy (NCI)</td> <td class="bodytext" bgcolor="#ffffff" valign="top"> Phase II melanoma</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">NCI Trial</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous and intraperitoneal administration monotherapy (NCI)</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I/II ovarian</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 012</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with cyclophosphamide</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Advanced malignancies including pancreatic, lung, ovarian</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 011
(Phase II)</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with paclitaxel and carboplatin</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase II head and neck</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 011</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with paclitaxel and carboplatin</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Advanced malignancies including melanoma, lung, ovarian</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 010</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with docetaxel</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Advanced malignancies including bladder, prostate, lung, upper gastro-intestinal</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 009</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration in combination with gemcitabine</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Advanced malignancies including pancreatic, lung, ovarian</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 008</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Local therapy in combination with radiation</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase II various metastatic tumours, including head & neck</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 007</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Infusion monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I/II recurrent malignant gliomas</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Ongoing</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 006</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Local therapy in combination with radiation</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I various metastatic tumours</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 005</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I various metastatic tumours</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.K.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 004</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Intravenous administration monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I various metastatic tumours</td> <td class="bodytext" bgcolor="#ffffff" valign="top">U.S.</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 003</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Local monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I recurrent malignant gliomas</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Canada</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 002</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Local monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">T2 prostate cancer</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Canada</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td> </tr> <tr> <td class="bodytext" bgcolor="#ffffff" valign="top">REO 001</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Local monotherapy</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Phase I trial for various subcutaneous tumours</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Canada</td> <td class="bodytext" bgcolor="#ffffff" valign="top">Complete</td></tr></tbody></table>

<dd class="abstract">
</dd>
Harmless Virus Could Be an Answer to Cancer

By MELLY ALAZRAKI Posted 11:00 AM 02/06/10


LINK


"We're working on a product that is widely applicable to quite a few indications of cancer and is based on a naturally occurring virus that's commonly found in the environment and that happens to have a preference of growing in cancer cells as opposed to growing in normal tissue."

It's called a reovirus (short for Respiratory Enteric Orphan virus), and it's a type which most people pick up by age 12 through inhalation or contact that causes few or no health problems. But when the virus enters cancer cells, it kills them.

On-Off Switch

Viruses, naturally, prefer cells that can't fight them off. And these cancer cells all have a common characteristic: They have a certain growth pathway, called the Ras pathway, turned on. "If a cell doesn't have that pathway turned on, nothing happens, so it's like an on-off switch for the virus's growth," Thompson explained. In the human body, very few normal cells have that Ras pathway turned on, and those die in the same amount of time the virus takes to kill them, so the body is not affected. "And that's where the story would end if only these few cells had the Ras pathway turned on all the time," Thompson added. "But it happens to be the state in most cancers."

"When the Ras pathway is turned on, it turns off the virus defense mechanism in the cell so the virus can go in and replicate itself," Thompson continued. It keeps replicating until its host -- the cancer cell -- is overwhelmed and dies, which happens within three days.
"Anywhere between two-thirds to 75% of the primary carcinomas -- ovarian, prostate, non-small cell lung cancer and so on -- actually have that pathway turned on," Thompson said. "In metastatic disease, which spreads beyond the primary tumor, it's between 95% to 100% that have the Ras pathway. So you have a disease that has this pathway, and a virus that for other reasons requires that pathway to grow."

Infecting the Cancer

That's where Oncolytics and its drug, Reolysin, come in play. Reolysin is "a variant of the virus we found in nature," explained Thompson. The treatment "is rather straightforward," he said. It involves five days of intravenous injections, and the side effects are few: Most commonly, patients run a small fever and feel a little tired.

Once the virus has killed the cancer cells, "the body actually clears the virus pretty effectively," Thompson explained, because the body mounts a normal immune response to the infection. "Normally, the latest we ever find the virus in the body is a couple of weeks after the first injection, and then it's completely gone," he says.



Thompson lost his mother and an uncle to cancer, and himself got melanoma. "Right after that, while the surgery was still healing in my leg, I got a call from a colleague of mine in the Alberta government asking me whether I would talk to this group of researchers at the University of Calgary who were working on a virus. I had very heightened sensitivity to cancer at that time and had expertise in the area. So I got a close look at it, and that's how I got involved in it."

"That's how Oncolytics started," he added. "In less than a year, we went public, cross-listed and did six financings."

Phase 3 Clinical Trial

The company has completed about a dozen early-phase clinical trials so far, and has seven to eight ongoing for a broad range of cancers, including melanoma, lung and ovarian. But the real test will be the upcoming Phase 3 clinical trial for head and neck cancer.

The study is designed to combine Reolysin with the standard chemotherapy care for head and neck. In earlier studies, the response rate to the treatment was 42% when Reolysin was added to common therapy, much higher than the average 10% response rate for the disease.

If that response rate holds up, no doubt patients would be eager for the drug to reach the market. "We could be selling product by 2012, if everything lines up properly," said Thompson. "The sad part about head and neck patients is that you know very quickly whether your product works on them or not. The patients we're looking at have a median life expectancy of 4.5 months, so you don't have to wait much to know whether your product had benefit for the patients."

(more at link)



1: Mol Ther. 2009 Jun;17(6):972-9. Epub 2009 Mar 17.http://www.ncbi.nlm.nih.gov/corehtml...ges-lo_npg.gif Links <dd class="ecxabstract"> Oncolytic reovirus effectively targets breast cancer stem cells.

Marcato P, Dean CA, Giacomantonio CA, Lee PW.
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Hence, novel cancer therapies will need to be tested for both tumor regression and CSC targeting. Herein we show that oncolytic reovirus that induces regression of human breast cancer primary tumor samples xenografted in immunocompromised mice also effectively targets and kills CSCs in these tumors. CSCs were identified based on CD24(-)CD44(+) cell surface expression and overexpression of aldehyde dehydrogenase. Upon reovirus treatment, the CSC population was reduced at the same rate as non-CSCs within the tumor. Immunofluorescence of breast tumor tissue samples from the reovirus- and mock-treated mice confirmed that both CSCs and non-CSCs were infectible by reovirus, and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay showed that both populations died by apoptosis. Ras, which has been shown to mediate reovirus oncolysis, was found to be present at similar levels in all cell types, and this is consistent with their comparable sensitivity to reovirus. These experiments indicate that oncolytic reovirus has the potential to induce tumor regression in breast cancer patients. More important, the CSC population was equally reduced and was as susceptible to reovirus treatment as the non-CSC population.
PMID: 19293772 [PubMed - indexed for MEDLINE]
</dd>

Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

Reovirus type 3 Dearing strain (ReoT3D) has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers.

Its human safety and potential efficacy are currently investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC).

Results: ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 +/- 0.12 ~ 2.68 +/- 0.25 (mean +/- SD) log10 pfu/cell.

Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent.

Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose) polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptoticcells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells.

Conclusions: These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

Author: Shizuko SeiJodie MussioQuan-en YangKunio NagashimaRalph ParchmentMatthew CoffeyRobert ShoemakerJoseph Tomaszewski
Credits/Source: Molecular Cancer 2009, 8:47



Oncolytics shares soar on cancer treatment trial news

Financial Post Published: Friday, October 02, 2009

OTTAWA - Shares of Calgary-based Oncolytics Biotech Inc. shot up Friday after the company announced it had reached an agreement with the U.S. Food and Drug Administration for the design of a Phase 3 trial involving its Reolysin cancer treatment.
"Oncolytics (ONC/TSX) is the first company to reach an agreement with the FDA on a Phase 3 trial design for an intravenously administered oncolytic virus under the SPA (special protocol assessment) process," Brad Thompson, chief executive of Oncolytics, said in a statement.
"This is an exciting step forward for our clinical program."
Shares of the Calgary-based firm rose as high as $4.10 in early morning trading in Toronto stock exchange, settling back to $3.70 by mid-afternoon.
The company said it will work with the FDA to develop trials to examine the effectiveness of its Reolysin treatment in combination with paclitaxel and carboplatin in patients with head and neck cancers, versus chemotherapy alone.
The main goal of the trial is to establish overall patient survival while secondary endpoints include response rates and safety and tolerability of Reolysin when used in combination.
The company said in a statement the study could eventually support a licence application submission for Reolysin, a virus that targets mostly solid-tumour cancers that have a tendency to spread, or metastasize, such as in head and neck tumours.
In previous tests, "the treatment combination has increased the response rate several fold compared to historical outcomes," the company said.

Looks like Tranilast might kill cancer stem cells:


<dl class="AbstractPlusReport"><dt class="head">1: Anticancer Drugs. 2009 Jun;20(5):334-45.http://www.ncbi.nlm.nih.gov/corehtml...ges-pmlogo.gif <script language="JavaScript1.2"><!-- var Menu19322072 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1932 2072&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Tranilast inhibits the growth and metastasis of mammary carcinoma.

<!--AuthorList-->Chakrabarti R, Subramaniam V, Abdalla S, Jothy S, Prud'homme GJ.
Department of Laboratory Medicine and Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Tranilast (N-[3,4-dimethoxycinnamonyl]-anthranilic acid) is a drug of low toxicity that is orally administered, and has been used clinically in Japan as an antiallergic and antifibrotic agent. Its antifibrotic effect is thought to depend on the inhibition of transforming growth factor-beta (TGF-beta). It has also been shown to exert antitumor effects, but its mode of action is unclear. Here, we explored the antitumor effects of tranilast in vitro and in vivo. Tranilast inhibited the proliferation of several tumor cell lines including mouse mammary carcinoma (4T1), rat mammary carcinoma stem cell (LA7), and human breast carcinoma (MDA-MB-231 and MCF-7). Tranilast blocked cell-cycle progression in vitro. In the highly metastatic 4T1 cell line, tranilast inhibited phospho-Smad2 generation, consistent with a blockade of TGF-beta signaling. It also inhibited the activation of MAP kinases (extracellularly regulated kinase 1 and 2 and JNK), which have been linked to TGF-beta-dependent epithelial-to-mesenchymal transition and, indeed, it blocked epithelial-to-mesenchymal transition. Although tranilast only partially inhibited TGF-beta production by 4T1 tumor cells, it potently inhibited the production of TGF-beta, interferon-gamma, IL-6, IL-10, and IL-17 by lymphoid cells, suggesting a general anti-inflammatory activity. In vivo, female BALB/c mice were inoculated with syngeneic 4T1 cells in mammary fat pads and treated with tranilast by gavage. Tranilast reduced (>50%) the growth of the primary tumor. However, its effects on metastasis were more striking, with more than 90% reduction of metastases in the lungs and no metastasis in the liver. Thus, tranilast has potential activity as an antimetastatic agent in breast cancer.</dd></dl>
Tranilast suppresses prostate cancer growth and osteoclast differentiation in vivo and in vitro.

<!--AuthorList-->Sato S, Takahashi S, Asamoto M, Naiki T, Naiki-Ito A, Asai K, Shirai T.
Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
BACKGROUND: In bone metastatic sites, prostate cancer cells proliferate on interacting with osteoclasts. Tranilast, which is used for an antiallergic drug, has been shown to inhibit growth of several cancers and stromal cells. The present study was conducted to assess suppressive effects of Tranilast on prostate cancer growth and osteoclast differentiation in vivo and in vitro. METHODS: In vivo, rat prostate cancer tissue was transplanted onto cranial bones of F344 rats and Tranilast was given for 9 days at doses of 0, 200, or 400 mg/kg/day. In vitro, human prostate cancer cell lines, LNCaP, PC3, and DU145, the rat prostate cancer cell line, PLS-10, and rat bone marrow cells were similarly treated with the agent. RESULTS: In vivo, tumor volumes were significantly decreased in the high dose group. While cell proliferation did not appear to be affected, apoptosis was induced and tumor necrosis was apparent. Cranial bone defects were decreased in the high dose group. In vitro, cell proliferation rates of all four cell lines were reduced by Tranilast and increased apoptosis was observed in LNCaP and PLS-10. In addition, Tranilast significantly reduced osteoclast differentiation of rat bone marrow cells. Western blot analysis of PLS-10 and LNCaP revealed that phospho-GSK3beta was up-regulated and phospho-Akt was down-regulated. CONCLUSIONS: Tranilast here suppressed rat prostate cancer growth and osteoclast differentiation. Growth of human prostate cancer cells was also inhibited. Thus, this agent deserves consideration as a candidate for conventional therapy of bone metastatic prostate cancer. Prostate (c) 2009 Wiley-Liss, Inc.
PMID: 19790239 [PubMed - as supplied by publisher]

Targeting Breast Cancer Stem Cells In Mice

05 Jun 2009 <input value="Click to Print" type="button">

Cancer develops when cells known as cancer stem cells begin to divide in an uncontrolled manner. Researchers from the University of Michigan Comprehensive Cancer Center have identified roles for the gene PTEN, which is already well known for its ability to suppress tumor growth, and for several pathways linked to PTEN in the growth of cells that give rise to breast cancer. The work, published in this week's issue of the open-access journal PLoS Biology, also reports that a drug that interferes with the activity of one of these pathways leads to a 90 percent decrease in the number of cells able to form tumors in mice.

PTEN is the most frequently inactivated tumor suppressor gene in several cancers, including breast cancer, where it is inactivated in about 40 percent of patients. PTEN inactivation is associated with poor patient outcomes, aggressive tumor growth, and resistance to chemotherapy and current targeted therapies.

Researchers first deleted PTEN from tumor cells grown in cell culture and from tumors in mice, and found an increase in the number cells able to form new tumors, which suggests that PTEN influences the cancer stem cell population. They also looked at pathways associated with PTEN and reported that the activity of the PI3-K/Akt pathway also regulates the size of the tumor-forming cell population by activating the Wnt pathway, another pathway previously implicated in multiple cancer types.

"Although there has been considerable progress in identifying cancer stem cells in a variety of tumor types, the pathways that drive the transformation of these cells are not well understood," says lead study author Hasan Korkaya, D.V.M., Ph.D., a research investigator in internal medicine at the University of Michigan Medical School.

Stem cells in breast cancer represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor's growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells.

In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone treatment showed no effect on the number of tumor-forming cells, but the addition of perifosine reduced the tumor-forming cell population by up to 90 percent. Additionally, cells treated with perifosine - either with or without docetaxel - were less likely to form tumors when reintroduced into mice when compared to cells treated with docetaxel alone. These results suggest that perifosine specifically targets the breast cancer stem cell population.

"This is most exciting since perifosine and other drugs that target this pathway are currently in clinical development. If cancer stem cells do contribute to tumor relapse, then adding drugs that target these cells may help to make our current therapies more effective," says study senior author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the University of Michigan Comprehensive Cancer Center.

Funding: This work was funded by the National Institutes of Health (NIH) grants CA129765 and CA101860, by the Taubman Institute, and in part by the University of Michigan Cancer Center NIH support grant 5 P 30 CA46592. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests statement: MSW holds equity in and is a scientific consultant for OncoMed Pharmaceuticals.

Citation:
"Regulation of Mammary Stem/Progenitor Cells by PTEN/Akt/b-Catenin Signaling."
Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, et al. (2009)
PLoS Biol 7(6): e1000121. doi:10.1371/journal.pbio.1000121

Source
Plos Biology <hr size="1">

http://www.keryx.com/images/page/ct-krx-0401.gif PERIFOSINE
To date, over 1,800 patients have been treated with KRX-0401 in trials conducted both in the United States and Europe. Its safety profile is distinctly different from that of most cytotoxic agents. KRX-0401 does not appear to cause flu-like symptoms, thrombocytopenia (decrease in platelets that may result in bleeding) or alopecia (hair loss); all of these toxicities occur frequently with many of the currently available treatments for cancer. The main side effects of KRX-0401 are nausea, vomiting, diarrhea and fatigue, but these are generally well-managed particularly at lower daily doses (50 mg or 100 mg) that have induced tumor regression. Responses have been seen with both daily and weekly regimens. At the doses studied, the daily regimens were better tolerated.

Seven Phase 1 single agent studies of KRX-0401 have been completed; three in Europe by Zentaris and four in the United States by the NCI, a department of the National Institutes of Health, or NIH, as part of a Cooperative Research and Development Agreement, or CRADA, and by us. These trials demonstrated that KRX-0401 can be safely given to humans with a manageable toxicity profile. The dose limiting toxicity in the Phase 1 studies was gastrointestinal: nausea, vomiting and diarrhea.

Thirteen Phase 1/2 studies of KRX-0401 in combination with other drugs have been conducted by Keryx. Agents that have been included in these combinations include gemcitabine, paclitaxel, docetaxel, prednisone, doxorubicin, capecitabine, pemetrexed, irinotecan, Doxil® (doxorubicin HCl liposome injection), trastuzumab, various endocrine therapies, imatinib, bortezomib, lenalidomide, sorafenib, and sunitinib. KRX-0401 has generally been well tolerated when used as a low daily dose (50 mg or 100 mg) in combination with these approved agents. KRX-0401 has also been studied in combination with radiotherapy without evidence of increased toxicity.

The NCI has completed a number of Phase 2 clinical trials studying KRX-0401 as a single agent, including studies in prostate, breast, head and neck and pancreatic cancers, as well as melanoma and sarcomas. In total, nine NCI clinical trials have been conducted across these six tumor types.

KRX-0401 has also been evaluated in ten Phase 2 clinical studies conducted by Keryx evaluating the single agent activity in various tumor types where patients have progressed on standard treatments. Clinical trials where responses have been reported have been conducted in patients with renal cell carcinoma, advanced brain tumors, soft-tissue sarcomas, hepatocellular carcinoma, as well as in hematologic malignancies including multiple myeloma and Waldenstrom's macroglobulinemia. As illustrated in the previous NCI trials, the lower daily doses (50 mg or 100 mg) have been better tolerated than the intermittent higher doses.

For information on KRX-0401 (Perifosine) clinical trials which are open and recruiting patients, please click here



Patients with other cancers posting on their trial experiences with perifosine:
http://www.cancercompass.com/message...all,1076,1.htm


<dl class="AbstractPlusReport"><dt class="head">1: PLoS Biol. 2009 Jun 2;7(6):e1000121. Epub 2009 Jun 2.http://www.ncbi.nlm.nih.gov/corehtml...oft_150x35.gif http://www.ncbi.nlm.nih.gov/corehtml...pubmed-pmc.gif <script language="JavaScript1.2"><!-- var Menu19492080 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["References for this PMC Article" , "window.top.location='/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=p ubmed_pubmed_refs&LinkReadableName=References%20fo r%20this%20PMC%20Article&IdsFromResult=19492080&or dinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubm ed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbs tractPlus' ", "", ""], ["Free in PMC" , "window.top.location='http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=19492080&i tool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPa nel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus&or dinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1949 2080&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.

<!--AuthorList-->Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS.
Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. hkorkaya@med.umich.edu
Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells.
PMID: 19492080 [PubMed - in process
</dd></dl>



Another study involving Perifosine:
<dl class="AbstractPlusReport"><dt class="head">1: Breast Cancer Res Treat. 2009 Jun 23. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...ringerlink.gif <script language="JavaScript1.2"><!-- var Menu19548083 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1954 8083&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation.

<!--AuthorList-->Wenzel J, Zeisig R, Haider W, Habedank S, Fichtner I.
Max-Delbrück-Center for Molecular Medicine Berlin-Buch, R.-Rössle-Strasse 10, 13122, Berlin, Germany, j.wenzel@mdc-berlin.de.
The process of metastasis formation in cancer is not completely understood and is the main reason cancer therapies fail. Previously, we showed that dual liposomes simultaneously containing the hemostatic inhibitor, dipyridamole and the anticancer drug, perifosine potently inhibited metastasis, causing a 90% reduction in the number of lung metastases in a murine experimental metastasis model. To gain deeper insight into the mechanisms leading to the inhibition of metastasis by these dual liposomes, in the present study, the development of metastases by MT3 breast cancer cells in a mouse xenograft model was analyzed in more detail with regard to tumor cell settlement and metastatic growth. We found that the development of lung metastases by MT3 tumor cells is essentially dependent on the formation of fibrin clots as a precondition for the pulmonary arrest of tumor cells and the subsequent intravascular expansion of micrometastases before their invasion into the surrounding tissue.
PMID: 19548083 [PubMed - as supplied by publisher
</dd></dl>

Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 22066
© 2008 American Society of Clinical Oncology
<table class="content_box_outer_table" align="right"> <tbody><tr> <td> <!-- beginning of inner table -->
</td></tr></tbody></table> <table cellpadding="0" cellspacing="0"><tbody><tr><td>Abstract

</td></tr></tbody></table>
Targeting notch signaling and estrogen receptor pathways in human breast cancer stem cells

<nobr>N. S. Luraguiz</nobr>, <nobr>T. Yong</nobr>, <nobr>H. Yin</nobr> and <nobr>A. Sun</nobr> Feist Weiller Cancer Center, LSUHSC, Shreveport, LA
22066
Background: Breast cancer stem cells have been identified asESA+CD44+CD24-Lin- cells, which may account for disease relapseand metastasis. Deregulation in stem cell self-renewal pathwayssuch as Notch, Wnt and Hedgehog signaling have been implicatedin mammary transformation. In humans, high levels of Notch1are associated with reduced patient survival. Inhibition ofNotch signaling has been proposed as a potential strategy intreating breast cancer. Tamoxifen, a modulator of estrogen receptor(ER), is currently used for the treatment of both early andadvanced ER+ breast cancer. It is unclear whether ER+ breastcancers originate from ER+ or ER- mammary stem/progenitor cells.Here, we investigate the molecular mechanisms of Notch signalingand ER interaction in breast cancer stem cells, and evaluateNotch inhibition and estrogen antagonist in targeting breastcancer stem cells. Methods: CD44+CD24- breast cancer stem cellsare isolated by flow cytometry sorting of (1) human breast cancercell line MDA-MB-231, (2) primary cells from invasive breastcancer lesions and (3) primary cells from benign breast tissues.Real-time PCR is performed to determine the expression of stemcell genes including genes in Notch pathway. IHC is performedto determine the ER and PR status of the cells. Stem like andnon-stem like cells are treated with GSI (a Notch inhibitor)and tamoxifen. The effects of the treatments on cell proliferationand apoptosis are determined by BrdU and Tunnel Assays. Resultsand Conclusion: Previously we have shown that GSI alone effectivelyinduced apoptosis in ER- MDA-MB-231 cells. Tamoxifen alone hadsubstantial killing effects on ER+ MCF7 cells, but enhancedkilling in both cell types were observed when treatments werecombined. Stem like, non stem-like and unsorted cells were treatedwith GSI, tamoxifen and combination of GSI and tamoxifen. Proliferationwas determined at 24 and 72 hours of treatment by BrdU assay.Stem-like cells exhibited significant sensitivity to GSI killingIn addition, an enhanced effect was observed when GSI was combinedwith tamoxifen, suggesting that chemotherapy that targets bothNotch signaling and estrogen receptor pathways in breast cancerstem cells may be an effective strategy in treating breast cancer.


J Med Chem. 2009 Jun 11;52(11):3441-4.
Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity.

Keown LE, Collins I, Cooper LC, Harrison T, Madin A, Mistry J, Reilly M, Shaimi M, Welch CJ, Clarke EE, Lewis HD, Wrigley JD, Best JD, Murray F, Shearman MS.
Department of Medicinal Chemistry, Molecular and Cellular Neuroscience, and in Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow, Essex, UK. keown.linda@yahoo.co.uk
The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.

PMID: 19432431 [PubMed - indexed for MEDLINE]


Exp Cell Res. 2009 Jul 15;315(12):2022-32. Epub 2009 Apr 22.
Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways.

Matsuoka H, Tsubaki M, Yamazoe Y, Ogaki M, Satou T, Itoh T, Kusunoki T, Nishida S.
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKCalpha and PKCdelta phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.

PMID: 19393235 [PubMed - indexed for MEDLINE]



Anticancer Drugs. 2009 Sep;20(8):723-35.
The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells.

Yde CW, Clausen MP, Bennetzen MV, Lykkesfeldt AE, Mouritsen OG, Guerra B.
Department of Biochemistry and Molecular Biology, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Tamoxifen resistance is a major clinical problem in the treatment of estrogen receptor alpha-positive breast tumors. It is, at present, unclear what exactly causes tamoxifen resistance. For decades, chlorpromazine has been used for treating psychotic diseases, such as schizophrenia. However, the compound is now also recognized as a multitargeting drug with diverse potential applications, for example, it has antiproliferative properties and it can reverse resistance toward antibiotics in bacteria. Furthermore, chlorpromazine can reverse multidrug resistance caused by overexpression of P-glycoprotein in cancer cells. In this study, we have investigated the effect of chlorpromazine on tamoxifen response of human breast cancer cells. We found that chlorpromazine worked synergistically together with tamoxifen with respect to reduction of cell growth and metabolic activity, both in the antiestrogen-sensitive breast cancer cell line, MCF-7, and in a tamoxifen-resistant cell line, established from the MCF-7 cells. Tamoxifen-sensitive and tamoxifen-resistant cells were killed equally well by combined treatment with chlorpromazine and tamoxifen. This synergistic effect could be prevented by addition of estrogen, suggesting that chlorpromazine enhances the effect of tamoxifen through an estrogen receptor-mediated mechanism. To investigate this putative mechanism, we applied biophysical techniques to simple model membranes in the form of unilamellar liposomes of well-defined composition and found that chlorpromazine interacts strongly with lipid bilayers of different composition leading to increased permeability. This implies that chlorpromazine can change influx properties of membranes hence suggesting that chlorpromazine may be a promising chemosensitizing compound for enhancing the cytotoxic effect of tamoxifen.

PMID: 19584708 [PubMed - indexed for MEDLINE]


<dl class="AbstractPlusReport"><dt class="head">1: Clin Cancer Res. 2009 Mar 15;15(6):2010-21. Epub 2009 Mar 10.http://www.ncbi.nlm.nih.gov/corehtml...nres_final.gif <script language="JavaScript1.2"><!-- var Menu19276287 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=19276287&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=19276287&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1927 6287&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab.

<!--AuthorList-->Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P, Sozzi G, Fontanella E, Menard S, Tagliabue E.
Molecular Biology Unit, Department of Experimental Oncology, IRCCS Foundation: National Cancer Institute, Milan, Italy.
PURPOSE: The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer. EXPERIMENTAL DESIGN: Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1 signaling inhibitor (GSI) or Notch1 small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed. RESULTS: In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following gamma-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants. CONCLUSIONS: Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.
PMID: 19276287</dd></dl><dl class="AbstractPlusReport"><dd class="abstract">
</dd><dd class="abstract">
Oncogene. 2008 Oct 16;27(47):6120-30. Epub 2008 Jun 30.
HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion.

Korkaya H, Paulson A, Iovino F, Wicha MS.
Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. hkorkaya@med.umich.edu
The cancer stem cell hypothesis proposes that cancers arise in stem/progenitor cells through disregulation of self-renewal pathways generating tumors, which are driven by a component of 'tumor-initiating cells' retaining stem cell properties. The HER2 gene is amplified in 20-30% of human breast cancers and has been implicated in mammary tumorigenesis as well as in mediating aggressive tumor growth and metastasis. We demonstrate that HER2 overexpression drives mammary carcinogenesis, tumor growth and invasion through its effects on normal and malignant mammary stem cells. HER2 overexpression in normal mammary epithelial cells (NMEC) increases the proportion of stem/progenitor cells as demonstrated by in vitro mammosphere assays and the expression of stem cell marker aldehyde dehydrogenase (ALDH) as well as by generation of hyperplastic lesions in humanized fat pads of NOD (nucleotide-binding oligomerization domain)/SCID (severe combined immunodeficient) mice. Overexpression of HER2 in a series of breast carcinoma cell lines increases the ALDH-expressing 'cancer stem cell' population which displays increased expression of stem cell regulatory genes, increased invasion in vitro and increased tumorigenesis in NOD/SCID mice. The effects of HER2 overexpression on breast cancer stem cells are blocked by trastuzumab in sensitive, but not resistant, cell lines, an effect mediated by the PI3-kinase/Akt pathway. These studies provide support for the cancer stem cell hypothesis by suggesting that the effects of HER2 amplification on carcinogenesis, tumorigenesis and invasion may be due to its effects on normal and malignant mammary stem/progenitor cells. Furthermore, the clinical efficacy of trastuzumab may relate to its ability to target the cancer stem cell population in HER2-amplified tumors.

PMID: 18591932 [PubMed - indexed for MEDLINE]


Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab

1. Alessandra Magnifico1,
2. Luisa Albano1,
3. Stefano Campaner4,
4. Domenico Delia2,
5. Fabio Castiglioni1,
6. Patrizia Gasparini3,
7. Gabriella Sozzi3,
8. Enrico Fontanella2,
9. Sylvie Menard1 and
10. Elda Tagliabue1

+ Author Affiliations

1. <address>Authors' Affiliation:¹Molecular Biology Unit, ²Molecular Cell Cycle Control Unit, and ³Molecular-Cytogenetics Unit, Department of Experimental Oncology, IRCCS Foundation: National Cancer Institute, and ⁴Department of Experimental Oncology, European Institute of Oncology, Milan, Italy </address>

1. Requests for reprints:
   Elda Tagliabue, Molecular Biology Unit, Department of Experimental Oncology, National Cancer Institute, Foundation IRCCS, Via Venezian 1, 20133 Milan, Italy. Phone: 390223903013; Fax: 390223903073; E-mail: elda.tagliabue@istitutotumori.mi.it.

Abstract

Purpose: The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer.
Experimental Design: Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1 signaling inhibitor (GSI) or Notch1 small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed.
Results: In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following γ-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants.
Conclusions: Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.




</dd></dl>

<dl class="AbstractPlusReport"><dt class="head">1: J Natl Cancer Inst. 2007 Apr 18;99(8):628-38.http://www.ncbi.nlm.nih.gov/corehtml...final_free.gif <script language="JavaScript1.2"><!-- var Menu17440164 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=17440164&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Gene" , "window.top.location='/sites/entrez?Db=gene&DbFrom=pubmed&Cmd=Link&LinkName=pub med_gene&LinkReadableName=Gene&IdsFromResult=17440 164&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubme d.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed _RVAbstractPlus' ", "", ""], ["Gene (GeneRIF)" , "window.top.location='/sites/entrez?Db=gene&DbFrom=pubmed&Cmd=Link&LinkName=pub med_gene_rif&LinkReadableName=Gene%20(GeneRIF)&Ids FromResult=17440164&ordinalpos=1&itool=EntrezSyste m2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Disco veryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["HomoloGene" , "window.top.location='/sites/entrez?Db=homologene&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_homologene&LinkReadableName=HomoloGene&I dsFromResult=17440164&ordinalpos=1&itool=EntrezSys tem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Dis coveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Nucleotide (RefSeq)" , "window.top.location='/sites/entrez?Db=nuccore&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_nuccore_refseq&LinkReadableName=Nucleotide% 20(RefSeq)&IdsFromResult=17440164&ordinalpos=1&ito ol=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPane l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Nucleotide (Weighted)" , "window.top.location='/sites/entrez?Db=nuccore&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_nuccore_weighted&LinkReadableName=Nucleotid e%20(Weighted)&IdsFromResult=17440164&ordinalpos=1 &itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results Panel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Protein (RefSeq)" , "window.top.location='/sites/entrez?Db=protein&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_protein_refseq&LinkReadableName=Protein%20( RefSeq)&IdsFromResult=17440164&ordinalpos=1&itool= EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.P ubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Protein (Weighted)" , "window.top.location='/sites/entrez?Db=protein&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_protein_weighted&LinkReadableName=Protein%2 0(Weighted)&IdsFromResult=17440164&ordinalpos=1&it ool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPan el.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=17440164&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["Taxonomy via GenBank" , "window.top.location='/sites/entrez?Db=taxonomy&DbFrom=pubmed&Cmd=Link&LinkName =pubmed_taxonomy_entrez&LinkReadableName=Taxonomy% 20via%20GenBank&IdsFromResult=17440164&ordinalpos= 1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Result sPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus ' ", "", ""], ["UniGene" , "window.top.location='/sites/entrez?Db=unigene&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_unigene&LinkReadableName=UniGene&IdsFromRes ult=17440164&ordinalpos=1&itool=EntrezSystem2.PEnt rez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPan el.Pubmed_RVAbstractPlus' ", "", ""], ["GEO Profiles" , "window.top.location='/sites/entrez?Db=geo&DbFrom=pubmed&Cmd=Link&LinkName=pubm ed_geo&LinkReadableName=GEO%20Profiles&IdsFromResu lt=17440164&ordinalpos=1&itool=EntrezSystem2.PEntr ez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPane l.Pubmed_RVAbstractPlus' ", "", ""], ["Cited in PMC" , "window.top.location='http://www.pubmedcentral.gov/tocrender.fcgi?action=cited&tool=pubmed&pubmedid=1 7440164&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstra ctPlus&ordinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1744 0164&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer.

<!--AuthorList-->Scaltriti M, Rojo F, Ocaña A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramon y Cajal S, Arribas J, Baselga J.
Medical Oncology Program, Medical Oncology Department, Vall d'Hebron University Hospital and Research Institute, Barcelona 08035, Spain.
BACKGROUND: Women with HER2-overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2-overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents. METHODS: MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided. RESULTS: Treatment of p95HER2-expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [CI] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% CI = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm3, difference = 146.2 mm3, CI = 73.8 to 218.5 mm3, P = .002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P = .029). CONCLUSIONS: Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies.
PMID: 17440164
</dd></dl>

U-M researchers link pathway to breast cancer stem cells

Drug that inhibits this pathway shown to reduce stem cell population

added 6/01/09 Ann Arbor - A gene well known to stop or suppress cancer plays a role in cancer stem cells, according to a new study from the University of Michigan Comprehensive Cancer Center. The researchers found that several pathways linked to the gene, called PTEN, also affected the growth of breast cancer stem cells.

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Max S. Wicha, M.D.

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Further, by using a drug that interferes with that pathway, the researchers produced an up to 90 percent decrease in the number of cancer stem cells within a tumor.
The study appears in the June issue of PLoS Biology, a journal from the Public Library of Science.
PTEN is the most frequently inactivated tumor suppressor gene in several cancers, including breast cancer, where it is inactivated in about 40 percent of patients. PTEN is linked to poor outcomes and is associated with aggressive cancers resistant to chemotherapy and current targeted therapies.
The U-M researchers deleted PTEN in tumors grown in cell cultures and in mice, and found an increase in the number of stem cells. They also looked at pathways associated with PTEN and reported that a pathway called PI3-K/Akt regulated the cancer stem cell population by activating another stem cell pathway, Wnt, which is also implicated in multiple cancer types.
"Although there has been considerable progress in identifying cancer stem cells in a variety of tumor types, the pathways that drive the transformation of these cells are not well understood," says lead study author Hasan Korkaya, D.V.M., Ph.D., research investigator in internal medicine at the U-M Medical School.
Researchers at U-M were the first to identify stem cells in breast cancer. These cells represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor’s growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells.
In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone showed no effect on the number of cancer stem cells in the tumor. But adding perifosine reduced the cancer stem cell population by up to 90 percent.
What's more, the cells treated with perifosine – either with or without docetaxel – were less likely to grow a secondary tumor, compared to the cells treated with just docetaxel.
"This is most exciting since perifosine and other drugs that target this pathway are currently in clinical development. If cancer stem cells do contribute to tumor relapse, then adding drugs that target these cells may help to make our current therapies more effective," says study senior author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.

Breast cancer U-M Cancer AnswerLine, 800-865-1125





Similar article: http://www.sciencedaily.com/releases...0601211427.htm
<dl class="EC_AbstractPlusReport"><dt class="head">
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</dt><dt class="head">1: PLoS Biol. 2009 Jun 2;7(6):e1000121. Epub 2009 Jun 2.http://www.ncbi.nlm.nih.gov/corehtml...oft_150x35.gif http://www.ncbi.nlm.nih.gov/corehtml...pubmed-pmc.gif Links
</dt><dd class="EC_abstract"> Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.

Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS.
Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. hkorkaya@med.umich.edu
Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells.
PMID: 19492080 [PubMed - in process]
</dd><dd class="EC_abstract">
</dd><dt class="head">
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">1: Orv Hetil. 2009 Feb 22;150(8):373-8.http://www.ncbi.nlm.nih.gov/corehtml...-ohlinkout.jpg <script language="JavaScript1.2"><!-- var Menu19218147 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=19218147&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=19218147&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1921 8147&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Akt enzyme: new therapeutic target in cancer and diabetes?


<!--AuthorList-->Cseh A, Szebeni B, Szalay B, Vásárhelyi B.
Semmelweis Egyetem, Altalános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest Bókay u. 54. 1083, Hungary. sceharon@gmail.com
Alteration of apoptotic processes plays a central role in the development and progression of several chronic disorders. Proteins responsible for the regulation of apoptosis are therapeutic targets; these include the Akt enzyme. Akt enzyme is expressed in most cell types. Akt activation is regulated by growth factors, insulin, and also environmental factors as altered oxygen tension and high temperature. Akt is a central regulator of cellular metabolism and survival. Akt function is reportedly altered in some disorders. An increased activity of Akt has been described in prostate, breast, colon, and pancreatic cancer, as well as in hematological malignancies. Akt is also a factor in the pathomechanism of diabetes as it determines beta-cell apoptosis of Langerhans islets and insulin sensitivity of the cells. Several studies revealed that some of the marketed drugs including statins, thiazolidinediones and ACE inhibitors modulate Akt activity. There are efforts to develop specific Akt inhibitors that may improve the efficacy of chemotherapy. Triciribine and perifosine are two Akt inhibitors in developmental phase 1 and 2 that may improve survival in breast cancer, pancreas cancer, gastrointestinal stroma tumor, sarcoma and melanoma, and in hematological malignancy.
PMID: 19218147 [PubMed - indexed for MEDLINE]
</dd><dd class="EC_abstract">

</dd></dl>

maybe different from BC and not sure of dosage but...
 

<dl class="AbstractPlusReport"><dt class="head">1: Int J Cancer. 2009 Feb 27;125(3):717-722. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...nce_150x34.gif <script language="JavaScript1.2"><!-- var Menu19431142 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1943 1142&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells.

<!--AuthorList-->Lomonaco SL, Finniss S, Xiang C, Decarvalho A, Umansky F, Kalkanis SN, Mikkelsen T, Brodie C.
William and Karen Davidson Laboratory of Cell Signaling and Tumorigenesis, Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, MI.
Malignant gliomas are characterized by a short median survival which is largely impacted by the resistance of these tumors tochemo- and radiotherapy. Recent studies suggest that a small subpopulation of cancer stem cells, which are highly resistant to gamma-radiation, has the capacity to repopulate the tumors and contribute to their malignant progression. gamma-radiation activates the process of autophagy and inhibition of this process increases the radiosensitivity of glioma cells; however, the role of autophagy in the resistance of glioma stem cells (GSCs) to radiation has not been yet reported. In this study we examined the induction of autophagy by gamma-radiation in CD133+ GSCs. Irradiation of CD133+ cells induced autophagy within 24-48 hr and slightly decreased the viability of the cells. gamma-radiation induced a larger degree of autophagy in the CD133+ cells as compared with CD133- cells and the CD133+ cells expressed higher levels of the autophagy-related proteins LC3, ATG5 and ATG12. The autophagy inhibitor bafilomycin A1 and silencing of ATG5 and beclin1 sensitized the CD133+ cells to gamma-radiation and significantly decreased the viability of the irradiated cells and their ability to form neurospheres. Collectively, these results indicate that the induction of autophagy contributes to the radioresistance of these cells and autophagy inhibitors may be employed to increase the sensitivity of CD133+ GSCs to gamma-radiation. (c) 2009 UICC.
PMID: 19431142 [PubMed - as supplied by publisher
</dd></dl>

Toxins (Got Ricin?)
 

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Sci. 2009 May 19. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...nce_150x34.gif <script language="JavaScript1.2"><!-- var Menu19459847 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1945 9847&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Humanized immunotoxins: A new generation of immunotoxins for targeted cancer therapy.

<!--AuthorList-->Mathew M, Verma RS.
Stem Cell and Molecular Biology Laboratory, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, India.
Chemotherapy, radiation, and surgery are the conventional treatment modalities for cancer. The success achieved with these approaches has been limited due to several factors like chemoresistance to drugs, non-specificity leading to peripheral toxicity, and non-resectable tumors. To combat these problems, the concept of targeted therapy using immunotoxins was developed. Immunotoxins are chimeric proteins with a cell-selective ligand chemically linked or genetically fused to a toxin moiety and can target cancer cells overexpressing tumor-associated antigens, membrane receptors, or carbohydrate antigens. Ligands for these receptors or monoclonal antibodies or single chain variable fragments directed against these antigens are fused with bacterial or plant toxins and are made use of as immunotoxins. Pseudomonas exotoxin, anthrax toxin, and diphtheria toxin are the commonly used bacterial toxins. Ricin, saporin, gelonin, and poke weed antiviral protein are the plant toxins utilized in immunotoxin constructs. Several such fusion proteins are in clinical trials, and denileukin difitox is a FDA-approved fusion protein. In spite of the promise shown by bacterial- and plant toxin-based chimeric proteins, their clinical application is hampered by several factors like immunogenicity of the toxin moiety and non-specific toxicity leading to vascular leak syndrome. In order to overcome these problems, a novel generation of immunotoxins in which the cytotoxic moiety is an endogenous protein of human origin like proapoptotic protein or RNase has been developed. This review summarizes the advances in this new class of fusion protein and the future directions to be explored. (Cancer Sci 2009).
PMID: 19459847 [PubMed - as supplied by publisher]
</dd></dl>

HER-2, Notch, and Breast Cancer Stem Cells: Targeting an Axis of Evil

<nobr>Hasan Korkaya</nobr> and <nobr>Max S. Wicha</nobr> Authors' Affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
Requests for reprints: Max S. Wicha, Department of Internal Medicine/Oncology, Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0015. Phone: 734-647-9923; Fax: 734-647-9480; E-mail: mwicha@med.umich.edu<script type="text/javascript"><!-- var u = "mwicha", d = "med.umich.edu"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>.
Abstract
Increasing evidence indicates that tumor-initiating (cancerstem) cells may contribute to treatment resistance and relapse,suggesting that improved clinical outcome will require effectivetargeting of this cell population. Recent studies suggest thatthe remarkable clinical efficacy of trastuzumab may relate toits ability to target cancer stem cell populations.

1. » Abstract
2. Full Text
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4. Related Article



<dl class="AbstractPlusReport"><dt class="head">1: J Natl Cancer Inst. 2008 May 7;100(9):672-9. Epub 2008 Apr 29.http://www.ncbi.nlm.nih.gov/corehtml...pen_access.gif <script language="JavaScript1.2"><!-- var Menu18445819 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=18445819&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=18445819&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["Cited in PMC" , "window.top.location='http://www.pubmedcentral.gov/tocrender.fcgi?action=cited&tool=pubmed&pubmedid=1 8445819&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstra ctPlus&ordinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1844 5819&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.

<!--AuthorList-->Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC.
Breast Center at Baylor College of Medicine, 1 Baylor Plaza BCM 600, TX 77030, USA.
BACKGROUND: Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44(>)/CD24(>/low)) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44(>) and CD24(>/low) cell population. METHODS: Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. RESULTS: Chemotherapy treatment increased the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non-statistically significant decrease in the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a statistically non-significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). CONCLUSION: These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
PMID: 18445819 [PubMed - indexed for MEDLINE]</dd></dl>
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What are the clinical implications of breast-cancer stem cells?


Kathryn Senior

<hr align="left" width="16%">


PII S1470-2045(08)70141-4
DOI 10.1016/S1470-2045(08)70141-4

<hr size="1">The number of breast-cancer stem cells expressing the CD44+/CD24-/low marker decreased in women with primary breast cancer after treatment with lapatinib, reported researchers at the 6th European Breast Cancer Conference (Berlin, Germany; April 15–19, 2008).
“The activity of lapatinib, an epidermal growth factor receptor (EGFR)/ERBB2 tyrosine-kinase inhibitor, suggests that targeting specific signalling pathways responsible for self renewal of these cells could provide a therapeutic strategy for eliminating breast-cancer stem cells”, says Jenny Chang (Baylor College of Medicine, Houston, TX, USA) co-author on the lapatinib study. Max Wicha (University of Michigan, Ann Arbor, MI, USA) agrees: “this is consistent with our findings that ERBB2 is an important regulator of the breast-cancer stem-cell phenotype”…

<table width="100%" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td valign="middle" align="left">Web address:
http://www.sciencedaily.com/releases/2009/05/
090519172051.htm</td> <td id="printbutton" valign="middle" align="right"><input value="Print this page" onclick="window.print()" type="button"></td> </tr></tbody></table> Adult Stem Cells From Bone Marrow Made To Kill Metastatic Lung Cancer Cells In Mice

ScienceDaily (May 22, 2009) — Researchers in London have demonstrated the ability of adult stem cells from bone marrow (mesenchymal stem cells, or MSCs) to deliver a cancer-killing protein to tumors. The genetically engineered stem cells are able to home to the cancer cells, both in culture and in mouse models, and deliver TNF-related apoptosis-inducing ligand (TRAIL), destroying the tumor cells while sparing normal cells.
The research will be presented on May 19, at the American Thoracic Society's 105th International Conference in San Diego.
"Present oncological therapies are limited by host toxicity," said Michael Loebinger, M.D., M.A, who, along with S. M. Janes, M.D., Ph.D., conducted the research at the Centre for Respiratory Research at the University College of London. "They are also limited by cancer resistance and may not destroy cancer stem cells."
With these experiments, the investigators combined two disparate areas of research that they believed held promise for treating cancer. Studies had shown that MSCs can be used as vectors to deliver anti-tumor therapy, while other studies found that TRAIL killed cancer cells, but not normal cells.
For their experiments, Drs. Loebinger and Janes identified those cells likely to be resistant to therapies (cancer cells that have characteristics of stem cells) and found that they were just as likely to be destroyed as tumor cells by this novel therapy.
In culture, the stem cells caused lung, squamous, breast and cervical cancer cells to die (all p< 0.01), even at low stem cell/tumor cell ratios (1:16).
In mice, the researchers showed that the stem cells could reduce the growth of subcutaneous breast tumors by approximately 80 percent (p< .0001). The stem cells could also be injected intravenously as therapy for mice with lung metastases and could eliminate lung metastases in 38 percent of mice compared to control mice, all of which still had metastases (p=0.03).
It is the first study to intravenously introduce MSCs that have been genetically modified to deliver TRAIL. Drs. Loebinger and Janes chose the breast cancer cells for both models because in their in vitro experiments, the MSCs "demonstrated a particularly strong homing to breast cancer cells."
"Breast cancer tumors are a good model of metastases," added Dr. Loebinger, "but our plan is to test the engineered stem cells with other models, including lung cancer."
While not fully understood, Dr. Loebinger added, the homing of the engineered cells appears to be a characteristic of MSCs themselves.
The authors conclude that, "this is the first study to demonstrate a significant reduction in tumor burden with inducible TRAIL-expressing MSCs in a well-controlled and specifically directed therapy."
They believe that human trials of TRAIL-expressing MSCs could begin in two or three years.

Lapatinib May Target Breast Cancer Stem Cells

Zosia Chustecka

April 18, 2008 — Results from a small clinical trial of 45 patients with locally advanced breast cancer suggests that the novel agent lapatinib (Tykerb, GlaxoSmithKline) has an effect on tumor-causing breast cancer stem cells.
"We saw significant tumor regression after 6 weeks with single-agent lapatinib," Angel Rodriguez, MD, from the Baylor College of Medicine, in Houston, Texas, reported yesterday at the 6th European Breast Cancer Conference (EBCC) in Berlin, Germany.
Lapatinib is available in the United States but not yet in Europe. In the United States, lapatinib is indicated for use in combination with capecitabine in advanced or metastatic breast cancer overexpressing HER-2 in women who have already been treated with an anthracycline, a taxane, and trastuzumab. The drug is expected to be approved in Europe soon; the European Medicines Agency issued a positive opinion in December 2007 for use of the drug in advanced or metastatic HER-2 breast cancer.
In the current study, lapatinib was given at a much earlier disease stage than specified in its licensed indication. Dr. Rodriguez and colleagues used lapatinib in a neoadjuvant setting for locally advanced cancer, and gave the drug as a single agent for 6 weeks, followed by a combination of weekly trastuzumab and 3-weekly docetaxel for 12 weeks before primary surgery.
A core biopsy taken after the 6 weeks of lapatinib therapy showed significant tumor regression, the researchers reported. Bidimensional tumor measurements showed a median decrease of 60.8%. In addition, there was a decrease in the tumorigenic CD44+/CD24–/low breast cancer cells (considered to be stem cells), from 10.6% to 4.7%, and a reduced self-renewal capacity as measured by mammosphere formation assays (reduced from 30 to 15 mammosphere/10,000 cells; P = .01).
The researchers had previously found that the tumorigenic CD44+/CD24–/low cells were resistant to conventional chemotherapy. "Indeed, residual cancers that were exposed to such chemotherapy showed an increase in the tumor-causing cells and enhanced tumor initiation by the formation of mammospheres (small tumors that form when tumor-causing cells are cultured in a test tube), which reflect the capacity of the cells to self-renew. So we were excited to see that the results with lapatinib were different," Dr. Rodriguez commented in a statement.
Analysis of surgically removed tissue showed a pathological complete response rate of 63% (16/25) after lapatinib and trastuzumab/decetaxel therapy, a rate that was "much higher than expected," the researchers told the meeting.
"Contrary to conventional chemotherapy, human breast cancer specimens obtained from this prospective in vivo study have demonstrated for the first time that lapatinib decreases tumorigenic breast cancer stem cells in the primary breast cancers of women receiving neoadjuvant treatment," Dr. Rodriguez and colleagues concluded.
"This indicates that the stem cells themselves should be the specific target," Dr. Rodriguez commented, "rather than a broad-brush approach, in which cells are killed indiscriminately. Targeting the stem cells may be more effective and could also prevent some of the unpleasant side effects associated with conventional chemotherapy."
Asked to comment on these findings, Dr. Emiel Rutgers, MD, PhD, from the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, in Amsterdam, who chaired the EBCC meeting, said: "If this is true — and it needs to be confirmed — then this is a bonus." The contention here is that such a response to just 6 weeks of lapatinib monotherapy — which wasn't expected — is due to the very basic and aggressive cancer stem cells being 'switched off'," he commented.
"However, one of the weak points in this research is that we talk about cancer stem cells, but we don't really know where they are," Dr. Rutgers told Medscape Oncology in an interview. "There is a lot of work supporting this concept, but if you ask me where the stem cell is in a tumor, well that's not so easy.... It's all conceptual. But it's a nice concept and a lot of research fits in with this concept, so there must be something true in it."
The response seen to lapatinib alone bodes well for the ongoing ALTTO study involving 8000 women, Dr. Rutgers commented. This study is comparing lapatinib with trastuzumab (Herceptin, Roche), both together and alone, in the adjuvant setting. However, the group in this study that involves monotherapy with lapatinib has been criticized, and some doctors have been reluctant to recruit women into this trial because they believe that there isn't enough evidence that lapatinib alone is effective. "So this latest bit of information will really help us to go forward with the ALTTO trial," Dr. Rutgers said.
6th European Breast Cancer Conference (EBCC): Abstract 204. Presented April 17, 2008.

http://alttotrials.com/patients.php#5


Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment.

Camara O, Jörke C, Hammer U, Egbe A, Rabenstein C, Runnebaum IB, Hoeffken K, Pachmann K.
Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany.
BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. CONCLUSIONS: In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

PMID: 18936973 [PubMed - indexed for MEDLINE]

Pancreatic cancer stem
cells therapy

Combination drug may target specific
cells

Updated: Friday, 29 May 2009, 8:57 PM EDT
Published : Friday, 29 May 2009, 8:52 PM EDT
(NCI) - A new drug combination tested in mice may target the cells responsible for driving some pancreatic tumors. The combination of gemcitabine and the experimental drug tigatuzumab eliminated populations of cancer stem cells and reduced tumor growth in a mouse model of pancreatic cancer, researchers from the Johns Hopkins Sidney Kimmel Cancer Center reported at the AACR annual meeting.
The results provide a rationale for testing the promising combination in patients with this deadly disease, Dr. Rajesh Kumar NV and his colleagues concluded.
Cancer stem cells are thought to self renew while giving rise to tumors, and they may resist conventional treatments. The researchers found that human pancreatic cancer stem cells overexpress a protein called death receptor-5 (DR-5), which is involved in programmed cell death (apoptosis). The protein is also the target of tigatuzumab, a humanized monoclonal antibody also known as CS-1008.
To evaluate the drug’s effects on these important cells, mice were given tigatuzumab alone, gemcitabine alone, or a combination. Although gemcitabine reduced tumor size, it increased levels of pancreatic cancer stem cells (as defined by the protein markers ALDH, CD24, and CD44), and all of the tumors recurred. The combination treatment, however, led to long-term remissions in half of the treated mice.
In addition, cancer stem cells were eliminated in mice that received tigatuzumab plus gemcitabine, which is the first-line treatment for patients with advanced pancreatic cancer. “It appears that tigatuzumab may be one of the first monoclonal antibodies to target cancer stem cells,” said Dr. Kumar NV. The drug is being tested in a phase II clinical trial with patients who have inoperable, untreated pancreatic cancer.


http://www.cancer.gov/ncicancerbulletin/042109/page3


Combination Therapy Targets Pancreatic Cancer Stem Cells

http://www.cancer.gov/images/documen.../aacr_logo.jpg A new drug combination tested in mice may target the cells responsible for driving some pancreatic tumors. The combination of gemcitabine and the experimental drug tigatuzumab eliminated populations of cancer stem cells and reduced tumor growth in a mouse model of pancreatic cancer, researchers from the Johns Hopkins Sidney Kimmel Cancer Center reported at the AACR annual meeting.
The results provide a rationale for testing the promising combination in patients with this deadly disease, Dr. Rajesh Kumar NV and his colleagues concluded.
Cancer stem cells are thought to self renew while giving rise to tumors, and they may resist conventional treatments. The researchers found that human pancreatic cancer stem cells overexpress a protein called death receptor-5 (DR-5), which is involved in programmed cell death (apoptosis). The protein is also the target of tigatuzumab, a humanized monoclonal antibody also known as CS-1008.
To evaluate the drug’s effects on these important cells, mice were given tigatuzumab alone, gemcitabine alone, or a combination. Although gemcitabine reduced tumor size, it increased levels of pancreatic cancer stem cells (as defined by the protein markers ALDH, CD24, and CD44), and all of the tumors recurred. The combination treatment, however, led to long-term remissions in half of the treated mice.
In addition, cancer stem cells were eliminated in mice that received tigatuzumab plus gemcitabine, which is the first-line treatment for patients with advanced pancreatic cancer. “It appears that tigatuzumab may be one of the first monoclonal antibodies to target cancer stem cells,” said Dr. Kumar NV. The drug is being tested in a phase II clinical trial with patients who have inoperable, untreated pancreatic cancer.

Breast cancer chemoresistance: Emerging importance of cancer stem cells
Surgical Oncology, 06/15/09

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Chuthapisith S et al. - Review presents the evidence for the involvement of cancer stem cells (CSCs) in carcinogenesis, tumour invasion and metastases, and resistance to various forms of therapies, including chemotherapy.
What are CSCs?

• Concepts of CSCs arose from the observations of the capacity to and comparability of self-renewal between stem cells and cancer cells
• A minority of tumor cells that are able to self renew and differentiate into a new tumor cell are termed CSCs

Role of CSCs in breast cancer chemoresistance:

• CSCs have a high level of ATP binding cassette (ABC) transporters that protect these cells from drug damage
• These cells remain quiescent in G-null phase
• They are later induced by different stimuli to differentiate into new mature chemoresistant tumor cells

Strategies to overcome chemoresistant breast cancer by targeting breast cancer stem cells:

• Traditional approach of switching to another drug does not work
• CSCs may be eliminated by selectively targeted therapies against various self-renewal signalling pathways including the Notch, Shh, BMI-1 and Wnt signalling pathways
• Targeting ABC transporter proteins may be another approach
• Biological therapy with monoclonal antibodies targeted against specific cellular surface molecules or receptors should be considered
• Targeting at the apoptotic pathway could be an attractive and therapeutically beneficial option

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Lett. 2009 Aug 8;280(2):134-44. Epub 2009 Apr 2.http://www.ncbi.nlm.nih.gov/corehtml...PubMedLink.gif <script language="JavaScript1.2"><!-- var Menu19345000 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1934 5000&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer.

<!--AuthorList-->Botrugno OA, Santoro F, Minucci S.
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Absent or altered differentiation is one of the major features of cancer cells. Histone deacetylases (HDACs) play a central role in the epigenetic regulation of gene expression. Aberrant activity of HDACs has been documented in several types of cancers, leading to the development of HDAC inhibitors (HDACi) as anti-tumor drugs. In vitro and in vivo experimental evidences show that HDACi are able to resume the process of maturation in undifferentiated cancer cells, justifying their introduction as differentiating agents in several clinical trials. Modulation of cell fate by HDACi is observed at several levels, including the stem cell compartment: HDACi can act both on cancer stem cells, and with the rest of the tumor cell mass, leading to complex biological outputs. As a note of caution, when used as single agent, HDACi show only a moderate and limited biological response, which is augmented in combinatorial therapies with drugs designed against other epigenetic targets. The optimal employment of these molecules may be therefore in combination with other epigenetic drugs acting against the set of enzymes responsible for the set-up and maintenance of epigenetic information.
PMID: 19345000</dd></dl>


J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):45-54. Epub 2009 Feb 28.
Resistance to endocrine therapy: are breast cancer stem cells the culprits?

O'Brien CS, Howell SJ, Farnie G, Clarke RB.

"A common theme of many investigations into CSCs is that they have inherent resistance to chemo and radiotherapy. This is proposed to be due to mechanisms such as more efficient DNA damage checkpoints and survival pathways compared to more differentiated tumor
cell populations."

"Enhanced interaction between estrogen receptor signalling and growth factor tyrosine kinase pathways such as EGFR, HER2/erbB2 and IGFR mediates resistance to endocrine therapy"

"HDAC inhibitors are being used in a number of on going clinical trials including a phase II trial evaluating vorinostat in ER positive patients with metastatic breast cancer who failed prior aromatase inhibitor therapy and up to three chemotherapy regimes [95]. A report of preliminary findings presented at ASCO 2008 showed that out of the 17 enrolled patients 21% had a partial response and 29% had stable disease after treatment with vorinostat 400 mg daily for 3 of 4 weeks and tamoxifen 20 mg daily,
continuously. These findings suggest that the addition of an HDAC inhibitor to tamoxifen in patients who have failed prior aromatase inhibitors or adjuvant tamoxifen may restore hormone sensitivity."<dl class="AbstractPlusReport"><dt class="head">
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">1: Clin Cancer Res. 2009 Apr 1;15(7):2488-96. Epub 2009 Mar 24.http://www.ncbi.nlm.nih.gov/corehtml...nres_final.gif <script language="JavaScript1.2"><!-- var Menu19318486 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1931 8486&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trial of valproic acid and epirubicin/FEC.

<!--AuthorList-->Munster P, Marchion D, Bicaku E, Lacevic M, Kim J, Centeno B, Daud A, Neuger A, Minton S, Sullivan D.
Division of Hematology Oncology, University of California, San Francisco, Divisadero, San Francisco, California 94143-1711, USA. pmunster@medicine.ucsf.edu
PURPOSE: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies. EXPERIMENTAL DESIGN: A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets. RESULTS: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid-associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression. CONCLUSION: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.
PMID: 19318486 </dd></dl><dl class="AbstractPlusReport"><dt class="head">
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">1: Cancer Lett. 2009 Aug 19. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...PubMedLink.gif <script language="JavaScript1.2"><!-- var Menu19699029 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1969 9029&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Troglitazone inhibits histone deacetylase activity in breast cancer cells.

<!--AuthorList-->Davies GF, Ross AR, Arnason TG, Juurlink BH, Harkness TA.
University of Saskatchewan, Department of Anatomy and Cell Biology, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
We previously demonstrated that the PPARgamma agonist Troglitazone (TRG), a potent antiproliferative agent, in combination with the anthracycline antibiotic Doxorubicin (DOX), is an effective killer of multiple drug resistant (MDR) human cancer cells. Cell killing was accompanied by increased global histone H3 acetylation. Presently, we investigated the epigenetic and cell killing effects of TRG in estrogen receptor (ER) positive MCF7 breast cancer cells. MCF7 cells were treated with the Thiazolidinediones (TZDs) TRG and Ciglitazone (CIG), the non-TZD PPARgamma agonist 15PGJ2, and the histone deacetylase inhibitors (HDACi's) Trichostatin A (TSA), sodium butyrate and PXD101. Using MTT cell viability assays, Western analyzes and mass spectrometry, we showed a dose-dependent increase in cell killing in TRG and HDACi treated cells, that was associated with increased H3 lysine 9 (H3K9) and H3K23 acetylation, H2AX and H3S10 phosphorylation, and H3K79 mono- and di-methylation. These effects were mediated through an ER independent pathway. Using HDAC activity assays, TRG inhibited HDAC activity in cells and in cell lysates, similar to that observed with TSA. Furthermore, TRG and TSA induced a slower migrating HDAC1 species that was refractory to HDAC2 associations. Lastly, TRG and the HDACi's decreased total and phosphorylated AKT levels. These findings suggest that TRG's mode of killing may involve downregulation of PI3K signaling through HDAC inhibition, leading to increased global histone post-translational modifications.
PMID: 19699029 [PubMed - as supplied by publisher]
</dd></dl>
Rezulin (troglitazone)

<!--checkmylinks1--><!--SS_BEGIN_ELEMENT(region1_element1)-->Parke-Davis/Warner Lambert agree to FDA's request to withdraw Rezulin from the market. FDA asked Parke-Davis/Warner Lambert to withdraw Rezulin after a review of recent safety data on Rezulin and two similar drugs, Avandia (rosiglitazone) and Actos (pioglitazone), showed that Rezulin is more toxic to the liver than the other two drugs. Data to date show that Avandia and Actos, both approved in the past year, offer the same benefits as Rezulin without the same risk.
[March 21, 2000 - News Release - FDA]




The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines

1. <address>^*Italfarmaco, SpA., 20092 Cinisello Balsamo, Italy; ^â€*Istituto Mario Negri, 20157 Milan, Italy; University of Brescia, 25123 Brescia, Italy; and ^‡University of Colorado Health Sciences Center, Denver, CO 80262</address>
2. <address>Contributed by Charles A. Dinarello</address>

Abstract

Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-containing hybrid polar molecule; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the production of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-α, IL-1-β, IL-6, and IFN-γ induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-α plus IFN-γ. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-α, IL-1-β, IL-12, and IFN-γ (50% reduction at 100–200 nM). The production of IFN-γ stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1-β precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addition, IFN-γ induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-α and IFN-γ in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1-β mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyperacetylate other targets.




Clin Cancer Res. 2010 Apr 13. [Epub ahead of print]
Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells.

Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, Sun D.
Authors' Affiliations: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan and Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan; and Department of Food Science and Technology, The Ohio State University, Columbus, Ohio.
Abstract

PURPOSE: The existence of cancer stem cells (CSCs) in breast cancer has profound implications for cancer prevention. In this study, we evaluated sulforaphane, a natural compound derived from broccoli/broccoli sprouts, for its efficacy to inhibit breast CSCs and its potential mechanism. EXPERIMENTAL DESIGN: Aldefluor assay and mammosphere formation assay were used to evaluate the effect of sulforaphane on breast CSCs in vitro. A nonobese diabetic/severe combined immunodeficient xenograft model was used to determine whether sulforaphane could target breast CSCs in vivo, as assessed by Aldefluor assay, and tumor growth upon cell reimplantation in secondary mice. The potential mechanism was investigated using Western blotting analysis and beta-catenin reporter assay. RESULTS: Sulforaphane (1-5 mumol/L) decreased aldehyde dehydrogenase-positive cell population by 65% to 80% in human breast cancer cells (P < 0.01) and reduced the size and number of primary mammospheres by 8- to 125-fold and 45% to 75% (P < 0.01), respectively. Daily injection with 50 mg/kg sulforaphane for 2 weeks reduced aldehyde dehydrogenase-positive cells by >50% in nonobese diabetic/severe combined immunodeficient xenograft tumors (P = 0.003). Sulforaphane eliminated breast CSCs in vivo, thereby abrogating tumor growth after the reimplantation of primary tumor cells into the secondary mice (P < 0.01). Western blotting analysis and beta-catenin reporter assay showed that sulforaphane downregulated the Wnt/beta-catenin self-renewal pathway. CONCLUSIONS: Sulforaphane inhibits breast CSCs and downregulates the Wnt/beta-catenin self-renewal pathway. These findings support the use of sulforaphane for the chemoprevention of breast cancer stem cells and warrant further clinical evaluation. Clin Cancer Res; 16(9); OF1-11. (c)2010 AACR.

PMID: 20388854 [PubMed - as supplied by publisher]



Environ Mol Mutagen. 2009 Apr;50(3):213-21.
Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds.

Nian H, Delage B, Ho E, Dashwood RH.
Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331-6512, USA.


FREE TEXT

Abstract

Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention.

PMID: 19197985 [PubMed - indexed for MEDLINE]PMCID: PMC2701665Free PMC Article

<dl class="AbstractPlusReport"><dt class="head">

</dt><dt class="head">PI3 k akt pathway inhibitin thought to work against CSCs:

</dt><dt class="head">

</dt><dt class="head">1: Thromb Res. 2008;122(2):191-202. Epub 2007 Nov 26.http://www.ncbi.nlm.nih.gov/corehtml...PubMedLink.gif <script language="JavaScript1.2"><!-- var Menu18031796 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=18031796&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Gene" , "window.top.location='/sites/entrez?Db=gene&DbFrom=pubmed&Cmd=Link&LinkName=pub med_gene&LinkReadableName=Gene&IdsFromResult=18031 796&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubme d.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed _RVAbstractPlus' ", "", ""], ["Gene (GeneRIF)" , "window.top.location='/sites/entrez?Db=gene&DbFrom=pubmed&Cmd=Link&LinkName=pub med_gene_rif&LinkReadableName=Gene%20(GeneRIF)&Ids FromResult=18031796&ordinalpos=1&itool=EntrezSyste m2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Disco veryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["HomoloGene" , "window.top.location='/sites/entrez?Db=homologene&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_homologene&LinkReadableName=HomoloGene&I dsFromResult=18031796&ordinalpos=1&itool=EntrezSys tem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_Dis coveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Nucleotide (RefSeq)" , "window.top.location='/sites/entrez?Db=nuccore&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_nuccore_refseq&LinkReadableName=Nucleotide% 20(RefSeq)&IdsFromResult=18031796&ordinalpos=1&ito ol=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPane l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Nucleotide (Weighted)" , "window.top.location='/sites/entrez?Db=nuccore&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_nuccore_weighted&LinkReadableName=Nucleotid e%20(Weighted)&IdsFromResult=18031796&ordinalpos=1 &itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Results Panel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Protein (RefSeq)" , "window.top.location='/sites/entrez?Db=protein&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_protein_refseq&LinkReadableName=Protein%20( RefSeq)&IdsFromResult=18031796&ordinalpos=1&itool= EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.P ubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Protein (Weighted)" , "window.top.location='/sites/entrez?Db=protein&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_protein_weighted&LinkReadableName=Protein%2 0(Weighted)&IdsFromResult=18031796&ordinalpos=1&it ool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPan el.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=18031796&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["Taxonomy via GenBank" , "window.top.location='/sites/entrez?Db=taxonomy&DbFrom=pubmed&Cmd=Link&LinkName =pubmed_taxonomy_entrez&LinkReadableName=Taxonomy% 20via%20GenBank&IdsFromResult=18031796&ordinalpos= 1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_Result sPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus ' ", "", ""], ["UniGene" , "window.top.location='/sites/entrez?Db=unigene&DbFrom=pubmed&Cmd=Link&LinkName= pubmed_unigene&LinkReadableName=UniGene&IdsFromRes ult=18031796&ordinalpos=1&itool=EntrezSystem2.PEnt rez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPan el.Pubmed_RVAbstractPlus' ", "", ""], ["GEO Profiles" , "window.top.location='/sites/entrez?Db=geo&DbFrom=pubmed&Cmd=Link&LinkName=pubm ed_geo&LinkReadableName=GEO%20Profiles&IdsFromResu lt=18031796&ordinalpos=1&itool=EntrezSystem2.PEntr ez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPane l.Pubmed_RVAbstractPlus' ", "", ""], ["Cited in PMC" , "window.top.location='http://www.pubmedcentral.gov/tocrender.fcgi?action=cited&tool=pubmed&pubmedid=1 8031796&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstra ctPlus&ordinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1803 1796&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Simvastatin induces apoptosis in human breast cancer cells in a NFkappaB-dependent manner and abolishes the anti-apoptotic signaling of TF/FVIIa and TF/FVIIa/FXa.

<!--AuthorList-->Aberg M, Wickström M, Siegbahn A.
Department of Medical Sciences, Clinical Chemistry and Pharmacology, Akademiska Hospital, S-751 85 Uppsala, Sweden.
INTRODUCTION: Statins have benefits independent of the plasma cholesterol properties among cancer patients and tissue factor (TF)/FVIIa induce PI3-kinase/AKT dependent anti-apoptosis during serum starvation. We analyzed how simvastatin induces apoptosis in human breast cancer cells and the influence of FVIIa and/or FXa on the proposed apoptosis. MATERIALS AND METHODS: MDA-MB-231 cells were serum starved or treated with 5 microM simvastatin and incubated with 10 and 100 nM FVIIa or 5/130 nM FVIIa/FX. RhoA was analyzed by confocal microscopy and caspase-3, nuclear fragmentation, and NFkappaB translocation were measured using the ArrayScan microscope. mRNA for BCL-2, AKT1 and TF were analyzed with RT-PCR or TaqMan. Protein levels and phosphorylation of PKB/AKT were determined by western blotting. RESULTS AND CONCLUSIONS: Simvastatin-induced apoptosis was recorded at 48 h in the MDA-MB-231 cells. Addition of FVIIa to the cells induced PKB/AKT phosphorylation at 24 h and rescued serum-deprived cells from apoptosis. However, in the presence of simvastatin we were unable to report any phosphorylation of PKB/AKT or anti-apoptotic effect mediated by the TF/FVIIa or TF/FVIIa/FXa complexes. This was due to a RhoA-dependent retention of NFkappaB to the cytosol at 12 h which led to a transcriptional down-regulation of the anti-apoptotic protein BCL-2 as well as reduced AKT1 mRNA production at 24 h and thus diminished levels of PKB/AKT protein. A transcriptional down-regulation of TF at 12 h possibly also contributed to the absent anti-apoptotic signaling. These results thereby support a role for simvastatin in cancer treatment and emphasize the importance of PKB/AKT in TF-signaling.
PMID: 18031796 [PubMed - indexed for MEDLINE]</dd></dl>

More on simvistatin:
<dl class="EC_AbstractPlusReport"><dt class="head">
</dt><dt class="head">1: Cancer Lett. 2007 Jun 8;250(2):220-8. Epub 2006 Nov 27.http://www.ncbi.nlm.nih.gov/corehtml...PubMedLink.gif Links
</dt><dd class="EC_abstract"> Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK.

Koyuturk M, Ersoz M, Altiok N.
Department of Histology and Embryology, Istanbul Science University, Faculty of Medicine, Istanbul, Turkey.
The effect of simvastatin, a widely used statin for the treatment of hypercholesterolemia, was investigated in the estrogen receptor (ER)-positive MCF-7, and the ER-negative MDA-MB 231 human breast cancer cell lines. Simvastatin induced cell cycle arrest and apoptosis in both cells. These effects of simvastatin were not altered by 17-beta-estradiol treatment. MCF-7 cells express wild-type tumor suppressor protein p53, whereas MDA-MB 231 cells carry a p53 mutation. However, no alteration in the level or localisation of p53 was observed with simvastatin treatment in either cell line. On the other hand, simvastatin strongly stimulated phosphorylation of c-jun which was completely abolished by the c-jun NH2-terminal kinase (JNK) inhibitor SP600125, which also significantly reduced the antiproliferative and apoptotic effects of simvastatin in these cells. In conclusion, we describe here that simvastatin induces apoptosis via involvement of JNK in breast cancer cells independent of their ER or p53 expression status. These findings indicate a great potential for statins for the treatment of cancers resistant to currently used drugs, and target the JNK signalling pathway for a novel approach of breast cancer treatment.
PMID: 17125918 [PubMed - indexed for MEDLINE
</dd></dl>

<dl class="AbstractPlusReport"><dt class="head">1: Stem Cells. 2009 Apr 23. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...nce_150x34.gif <script language="JavaScript1.2"><!-- var Menu19536809 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1953 6809&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Antigen-Specific T Cell Response from Dendritic Cell Vaccination Using Cancer Stem-like Cell-Associated Antigens.

<!--AuthorList-->Xu Q, Liu G, Yuan X, Xu M, Wang H, Ji J, Konda B, Black KL, Yu JS.
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Glioblastoma multiforme is the most aggressive primary brain tumor, with current treatment remaining palliative. Immunotherapies harness the body's own immune system to target cancers and could overcome the limitations of conventional treatments. One active immunotherapy strategy uses dendritic cell (DC)-based vaccination to initiate T cell-mediated anti-tumor immunity. It has been proposed that cancer stem-like cells (CSCs) may play a key role in cancer initiation, progression and resistance to current treatments. However, whether using human CSC antigens may improve the anti-tumor effect of DC vaccination against human cancer is unclear. In this study, we explored the suitability of CSCs as sources of antigens for DC vaccination again human GBM, with the aim of achieving CSC-targeting and enhanced anti-tumor immunity. We found that CSCs express high levels of tumor associated antigens (TAAs) as well as major histocompatibility complex (MHC) molecules. Furthermore, DC vaccination using CSC antigens elicited antigen-specific T cell responses against CSCs. DC vaccination induced interferon (IFN) -gamma production is positively correlated with the number of antigen-specific T cells generated. Finally, using a 9L CSC brain tumor model, we demonstrate that vaccination with DCs loaded with 9L CSCs, but not daughter cells or conventionally cultured 9L cells, induced CTLs against CSCs, and prolonged survival in animals bearing 9L CSC tumors. Understanding how immunization with CSCs generates superior anti-tumor immunity may accelerate development of CSC-specific immunotherapies and cancer vaccines.
</dd></dl>

June 18, 2009 08:00 AM Eastern Daylight Time http://www.businesswire.com/images/i..._permalink.gif
ImmunoCellular Therapeutics Announces Filing of Key Patent Application Relating to Cancer Stem Cell Technology


<!-- start story body -->LOS ANGELES--(BUSINESS WIRE)--ImmunoCellular Therapeutics, Ltd. (OTC: IMUC.OB) (IMUC), a biotechnology company, today announced the filing of a provisional U.S. patent application relating to its novel vaccine technology targeting cancer stem cells. The patent application relates to new peptide candidates that may significantly expand the potential target patient population for the company’s cancer stem cell vaccine product candidate, ICT-121. Many cancer therapies are limited by their ability to be used only in patients with certain human leukocyte antigen (HLA) types. Identification of the new peptides for use in IMUC’s vaccine should enable the use of IMUC’s product candidate in patients with many different HLA types. The Company currently has 25 issued or pending patents.
“This patent application supports our broad and growing portfolio of intellectual property. ICT-121 is an immunotherapy that targets cancer stem cells - a very exciting approach given the product’s mission of destroying cancer cells at their root as well as its proven ability in preclinical studies to be highly targeted for destroying cancer cells,” stated Manish Singh, Ph.D., president and chief executive officer of IMUC. “This product may have applicability to multiple types of cancer, but our first clinical target will be glioblastoma. We anticipate filing an Investigational New Drug (IND) application next quarter to begin a Phase I clinical trial of ICT-121.”
About ICT-121
ICT-121 is IMUC’s cancer stem cell (CSC) vaccine product candidate that consists of a peptide to stimulate a cytotoxic T-lymphocyte (CTL) response to CD133, which is generally overexpressed on the CSCs. It is designed as an “off-the-shelf” vaccine. IMUC will initially evaluate it in a Phase I clinical study for glioblastoma which the company expects to file an IND for in the third quarter of this year. While glioblastoma will be the initial target for ICT-121, CD133 is also overexpressed in colon cancer, breast cancer, liver cancer, prostate cancer, multiple myeloma and melanoma, providing many potential cancer targets for this CSC vaccine in the future.
About ImmunoCellular Therapeutics, Ltd.
IMUC is a Los Angeles-based clinical-stage company that is developing immune based therapies for the treatment of brain and other cancers. The company’s “off the shelf” therapeutic vaccine product candidate targeting cancer stem cells for multiple cancer indications is expected to enter clinical trials during the fourth quarter of 2009. IMUC is in pre-clinical development of a monoclonal antibody product candidate for the treatment of small cell lung cancer and pancreatic cancer, and is also evaluating its platform technology for monoclonal antibody discovery using differential immunization for diagnosing and treating multiple types of cancer. To learn more about IMUC, please visit www.imuc.com.




ImmunoCellular (IMUC.OB): Taking Aim At The Root Of Cancer
http://www.istockanalyst.com/article...icleid/3438149

1: J Immunother. 2009 May 28. [Epub ahead of print]

Honokiol-mediated Inhibition of PI3K/mTOR Pathway: A Potential Strategy to Overcome Immunoresistance in Glioma, Breast, and Prostate Carcinoma Without Impacting T Cell Function.



<dd class="abstract">
<!--AuthorList-->Crane C, Panner A, Pieper RO, Arbiser J, Parsa AT.
*Department of Neurological Surgery, University of California, San Francisco, CA daggerDepartment of Dermatology, Emory University School of Medicine, Atlanta, GA.
Inhibition of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is an appealing method for decreasing the immunoresistance and augmenting T cell-mediated immunotherapy. A major impediment to this strategy is the impact of conventional PI3K/mTOR pathway inhibitors on T cell function. In particular, rapamycin, is a well-known immunosuppressant that can decrease the activity of the PI3K/mTOR pathway in tumor cells, but also has a profound inhibitory effect on T cells. Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. Specifically, we show that at doses sufficient to down-regulate levels of phospho-S6 and the negative immune regulator B7-H1 in tumor cells, Honokiol does not significantly impair T cell proliferation or proinflammatory cytokine production. In contrast to classic inhibitors, including LY294002, wortmannin, AKT inhibitor III and rapamycin, Honokiol specifically decreases the PI3K/mTOR pathway activity in tumor cells, but not in freshly stimulated T cells. Collectively, our data define a unique application for Honokiol and provide the impetus to more fully elucidate the mechanism by which T cells are resistant to the effects of this particular inhibitor. Honokiol is clinically available for human testing and may serve to augment T cell-mediated cancer immunotherapy.
PMID: 19483651 [PubMed - as supplied by publisher


http://herbalmedicine.suite101.com/article.cfm/honokiol

Honokiol appears to be non toxic, easily absorbed, and systematically available. This is important since many promising materials like Epigallocatechin Gallate (EGCG) are not absorbed well in the digestive tract. Honokiol also avoids immediate clearing by the liver (first pass effect) and crosses blood barriers that often exclude other compounds.
Recent studies have explored honokiol and found validation for it as a treatment option for anxiety, cancer, peridontal disease, stroke, inflammation, and even weight loss.

Cancer Management

Honokiol has been effective in vitro and in vivo against several types of cancers. It appears to turn off the division of some cancer cells while inducing others to kill themselves (apoptosis). It has antiangiogenesis properties (eliminating the blood supply to tumors) and some studies are recommending it as adjunct treatment with other types of chemotherapy.

Clincancerres.aacrjournals.org/cgi/content/abstract/14/4/1248; Apoptosis
www.jbc.org/cgi/content/abstract/278/37/35501;Antiangiogenesis




</dd><dd class="abstract">Distinguishing Friend from Foe in the Battle Against Cancer

</dd><dd class="abstract">http://www.physorg.com/news77201870.html

</dd><dd class="abstract">excerpt:

</dd><dd class="abstract">Rapamycin, an immunosuppressant used to block organ rejection after transplants, also inactivates proteins stimulating cell division and in clinical trials has been combined with other drugs to halt cancer cell growth.
But to cancer cells, rapamycin is both friend and foe. “Rapamycin is not as successful as initially expected in treating cancer,” explains Ghosh. “Instead of killing cells, you end up triggering a survival response in them.” This study, however, suggests that taking NF-kB out of the game would make rapamycin less “friendly.”
“A major problem of chemotherapy is that sooner or later cancer cells develop resistance, which requires higher and higher doses of chemotherapeutics,” observes Verma, who is also an American Cancer Society professor in Salk's Laboratory of Genetics. “Rapamycin-mediated killing of cancer cells could be increased by inhibiting the function of NF-kB proteins. Our studies provide the basis for arriving at this very important conclusion, which has enormous bearing on cancer treatment.”
Tergaonkar concurs. “Our studies suggest the potential use of NF-kB signaling inhibitors as adjuvants to maximize the effect of rapamycin-based therapeutics. These findings will have a significant impact on human health.”


</dd>

http://www.news.com.au/perthnow/story/0,21598,25705164-949,00.html


Scientists closer to beating cancer

SYDNEY scientists have made a world breakthrough in the treatment of cancer that has potential to save tens of thousands of lives.
Working out of a suburban laboratory, they have perfected a therapy to destroy drug-resistant tumour cells.
Their new "trojan horse" therapy - which involves the sending of bacterially-derived nanocells into cancer cells in two separate waves - will be published in the July edition of the prestigious Nature Biotechnology medical journal.
The Daily Telegraph can reveal that the first human clinical trials involving 20 long-term cancer patients will start within weeks.
The treatment, based on nano-sized particles called EDVs, is the result of five years of research and experimentation by Dr Jennifer MacDiarmid and Dr Himanshu Brahmbhatt, at their biotech company EnGeneIC in Lane Cove.
"The beauty is that our EDVs (EnGeneIC delivery vehicles) operate like trojan horses ... they arrive at the gates of the affected cells and are always allowed in," Dr MacDiarmid and Dr Brahmbhatt said. "We're playing the rogue cells at their own game. They switch on the gene to produce the protein to resist drugs. We are switching off the gene which, in turn, enables the drugs to enter."
Conventional drug therapy can kill a large number of cancer cells but a small percentage of those cells produce proteins that make them resistant to chemotherapeutic drugs.
"Consequently, follow-up drug treatments can fail," Dr Brahmbhatt said. "The tumours thus become untreatable and continue to flourish, ultimately killing the patient."
Chairman of the Australian Cancer Research Foundation's medical research advisory committee Ian Fraser said yesterday the findings were a "significant breakthrough".
The benign nature of the EDV technology is expected to enable cancer sufferers to get on with their lives using out-patient therapy.
Over the past two years testing has been highly successful in experimental groups by using substantially lower concentrations of drug and antibodies than used in conventional treatments.
Similar success has been achieved in early-stage clinical case studies in dogs suffering from relapsed drug-resistant cancers.
The reversal of drug resistance, followed by chemotherapy, was extremely effective even in highly aggressive cancers and resulted in 100 per cent survival in mice.
Dr Brahmbhatt said: "Our methodology does not damage the normal cells and is applicable to a wide spectrum of solid cancer types. In the future it will help provide what is termed 'tailor-made medicine' geared to individual circumstances."


June 29, 2009
New Cancer Treatment Shows Promise in Testing

By NICHOLAS WADE
A new method of attacking cancer cells, developed by researchers in Australia, has proved surprisingly effective in animal tests.
The method is intended to sidestep two major drawbacks of standard chemotherapy: the treatment’s lack of specificity and the fact that cancer cells often develop resistance.
In one striking use of the method, reported online Sunday in Nature Biotechnology, mice were implanted with a human uterine tumor that was highly aggressive and resistant to many drugs. All of the treated animals were free of tumor cells after 70 days of treatment; the untreated mice were dead after a month.
The lead researchers, Jennifer A. MacDiarmid and Himanshu Brahmbhatt, say their company, EnGeneIC of suburban Sydney, has achieved a similar outcome in dogs with advanced brain cancer. “We have been treating more than 20 dogs and have spectacular results,” Dr. Brahmbhatt said. “Pretty much every dog has responded and some are in remission.” These experiments have not yet been published.
Cancer experts who were not involved with the research say that the new method is of great interest, but that many treatments that work well in laboratory mice turn out to be ineffective in patients.
Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, called the method “a creative and promising line of research,” but noted the general odds against success.
“Unfortunately our track record shows that far less than 1 percent of our promising approaches actually make the grade in patients,” he said.
The EnGeneIC researchers said they had conducted successful safety tests in a large number of monkeys and will start safety trials in patients with all kinds of solid tumors next month. in three Melbourne They said they had discussed licensing their technology with large pharmaceutical companies and others.
Stephen H. Friend, head of cancer research at Merck until early this year, said he had been following EnGeneIC’s work for more than a year, and praised the company for trying a method that others had written off without trying.
“I consider the approach is remarkable and more than intriguing,” said Dr. Friend, who is now at Sage Bionetworks in Seattle. But he warned that cancer cells are very versatile and can “evolve around any pressure you put on them,” so that no single approach is likely to afford a cure.
The EnGeneIC method uses minicells to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumors resistant to toxins.
The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells.
No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80 percent of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor.
The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever cargo the minicells carry.
What also helps direct the minicells toward tumors, the EnGeneIC researchers say, is that the blood vessels around tumors tend to be leaky, and the minicells are small enough to leave the circulation at the leak sites.
The minicells do not seem to be highly provocative to the immune system, even though they are made of bacterial cell membrane. The reason may be that the provocative parts of the membrane are masked by antibodies with which the minicells are coated, Dr. Brahmbhatt said.
In the experiments reported Sunday, EnGeneIC treated cancer-ridden mice with two waves of minicells. The first wave contained an agent that suppressed an important gene for toxin resistance. The gene makes a protein that pumps toxin out of cells, and is a major cause of the resistance that tumors often develop toward chemotherapeutic agents.
After the toxin-expelling gene had been knocked down in the tumor cells, the EnGeneIC researchers injected a second wave of minicells, each loaded with half a million molecules of doxorubicin, a toxin used in chemotherapy.
The two-wave treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether.
“The technology looks very good,” said Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island. It provides a general method of delivering chemicals to tumors, he said, especially those that are usually degraded in the bloodstream.
Dr. Stillman, who has advised EnGeneIC and is a co-author of its report, said the minicells could be particularly helpful for delivering silencing RNAs, a promising new class of drug that is rapidly destroyed in the body unless protected.
Though the minicells can be varied to attack different receptors and to import any gene of interest on elements called plasmids, the method still has several hurdles to jump.
Robert M. Hoffman, of the University of California, San Diego, said that the minicells were “good strategy and good science” but that the researchers had implanted the human tumors under the mice’s skin, a position from which they do not usually spread through the body. So the experiments do not answer the question of whether minicells can attack metastasized cancer, he said.
Dr. Hoffman, who is president of AntiCancer Inc., has obtained striking remissions with metastasized cancers in mice by treating them with salmonella bacteria. The bacteria have been engineered to lack two kinds of amino acid, which makes them unable to grow in normal tissues. In cancer cells, however, where the missing amino acids are in more plentiful supply, the bacteria are highly virulent and kill the cells.
The idea of treating cancer with bacteria goes back to the 19th century, when physicians noticed that cancer patients who became infected sometimes enjoyed a remission. Both Dr. Hoffman’s method and the minicells, in different ways, revisit these old observations. Both may face special scrutiny from regulators concerned at the prospect of putting bacteria into people.
Dr. Hoffman said his studies with the defective bacteria were going well and that his company might be ready to start a safety test in patients in two years if it can find a good partner. Use of bacteria in cancer “is an old story but there is definitely a lot of promise there,” he said.

<dl class="ecxAbstractPlusReport"><dt class="head">1: Cancer Sci. 2009 Sep 1. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...nce_150x34.gif Links
</dt><dd class="ecxabstract"> Oral delivery of tumor-targeting Salmonella exhibits promising therapeutic efficacy and low toxicity.

Chen G, Wei DP, Jia LJ, Tang B, Shu L, Zhang K, Xu Y, Gao J, Huang XF, Jiang WH, Hu QG, Huang Y, Wu Q, Sun ZH, Zhang JF, Hua ZC.
Jiangsu Center of Hepatobiliary Diseases and the State Key Laboratory of Pharmaceutical Biotechnology, Affiliated Gulou Hospital, Nanjing University, Nanjing 210093.
Tumor-targeting bacteria have been developed as powerful anticancer agents. Salmonella typhimurium VNP20009, a representative tumor-targeting strain, has been systemically administered as a single-agent therapy at doses of 1 x 10(6) to 3 x 10(6) colony-forming unit (cfu)/mouse, or in combination with other antitumor agents at doses of 1 x 10(4) to 2 x 10(5) cfu/mouse. Recently, we reported that oral delivery of VNP20009 at the dose of 1 x 10(9) cfu/mouse induced significant anticancer effects comparable to that induced by systemic administration of this strain at 1 x 10(4) cfu/mouse. To further address the efficacy and safety of oral administration of bacteria, here we performed a systemically comparative analysis of anticancer efficacy and toxicity of VNP20009 administered: (i) orally at a dose of 1 x 10(9) cfu/mouse (VNP9-oral); (ii) intraperitoneally at a dose of 1 x 10(4) cfu/mouse (VNP4-i.p.); or (iii) intraperitoneally at a dose of 1 x 10(6) cfu/mouse in tumor-free and tumor-bearing murine models. The results showed that VNP9-oral, similar to VNP4-i.p., induced significant tumor growth inhibition whereas VNP6-i.p. induced better anticancer effect in the B16F10 melanoma model. Among three treatments, VNP9-oral induced the mildest and reversible toxicity whereas VNP6-i.p. resulted in the most serious and irreversible toxicities when compared to other two treatments. Moreover, the combination of VNP9-oral with a low dose of chemotherapeutics produced comparable antitumor effects but displayed significantly reduced toxicity when compared to VNP6-i.p. The findings demonstrated that oral administration, as a novel avenue in the application of bacteria, is highly safe and effective. Moreover, the present preclinical study should facilitate the optimization of bacterial therapies with improved anticancer efficacy and reduced adverse effects in future clinical trials. (Cancer Sci 2009).
PMID: 19793349 [PubMed - as supplied by publisher
</dd></dl>

Researcher’s Discovery Points to a New Treatment Avenue for Acute Myeloid Leukemia
published in Cell Stem Cell July 2, 2009
<table class="border" cellpadding="5" cellspacing="1" width="100%"> <tbody><tr><td valign="top" width="50%"> Libraries
Medical News</td><td width="25">
</td><td valign="top">Keywords
LEUKEMIA, CANCER, STEM CELLS </td></tr><tr><td colspan="3" valign="top">Contact Information
Available for logged-in reporters only</td></tr><tr><td colspan="3" valign="top">Description
Dr. John Dick, Senior Scientist at the Ontario Cancer Institute, the research arm of Princess Margaret Hospital, co-led a multinational team that has developed the first leukemia therapy that targets a protein, CD123, on the surface of cancer stem cells that drive acute myeloid leukemia (AML), which is an aggressive disease with a poor outcome.<!-- AddThis Button BEGIN --> <script type="text/javascript">var addthis_pub = "srice"; var addthis_options = "email, favorites, digg, delicious, facebook, google, myspace, newsvine, reddit, slashdot, more";</script> http://s7.addthis.com/static/btn/lg-share-en.gif<script type="text/javascript" src="http://s7.addthis.com/js/152/addthis_widget.js"></script>
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</td> </tr> </tbody></table> Newswise — Dr. John Dick, Senior Scientist at the Ontario Cancer Institute, the research arm of Princess Margaret Hospital, co-led a multinational team that has developed the first leukemia therapy that targets a protein, CD123, on the surface of cancer stem cells that drive acute myeloid leukemia (AML), which is an aggressive disease with a poor outcome.
Dr. Richard Lock is leading the clinical trial in Australia that expands on research suggesting that antibodies targeting cancer stem cells significantly reduced the growth of human AML cells that had been transplanted into immune-deficient mice, a laboratory model that mimics the human disease, establishing the therapeutic potential of this type of therapy.
Dr. Tom Hudson, President and Scientific Director of the Ontario Institute for Cancer Research (OICR) congratulated Dr. Dick, who is the Program Leader of OICR’s Cancer Stem Cell Program. Dr. Hudson said, “John Dick has made remarkable progress in the understanding of what initiates and sustains cancer. Together with his collaborators Dr. Dick has developed the first anti-cancer monoclonal antibody therapy that specifically targets cancer stem cells. This discovery offers hope for the development of treatments that target the cancer stem cells of other types of tumours as well.”
“This is precisely the role we envisioned for the Ontario Institute for Cancer Research when the McGuinty government created it back in 2005,” said Minister of Research and Innovation John Milloy. “Bringing together this province’s considerable strengths around cancer prevention, detection, diagnosis and treatment is helping Ontario lead the fight against this terrible disease.”
The research on AML builds on the discovery by Dr. Dick that there is a population of cells within cancer, termed cancer stem cells, which are responsible for sustaining cancer growth. Their earlier research had shown that cancer stem cells are often resistant to standard chemotherapy and since they survive such therapy, they can eventually cause a recurrence of the disease.
The antibody targets the CD123 protein (IL-3 receptor α chain) on the cancer stem cells that drive cancer growth. The antibody does not appear to affect normal blood cells. On the basis of this experimental work, a Phase I clinical trial has been initiated to test safety and effectiveness in patients.
“The cancer stem cell hypothesis is one of the most exciting ideas in cancer biology, with the potential to truly transform cancer therapy. A major question has been whether agents could be developed that specifically target these cells without affecting normal stem cells,” said Dr. Benjamin Neel, Director of the Ontario Cancer Institute. “The work of Drs. Dick and Lock provides the first evidence that such therapies may be possible.”
The research paper Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells was published in Cell Stem Cell July 2, 2009.

Dendritic cell vaccines for cancer stem cells.

<!--AuthorList-->Pellegatta S, Finocchiaro G.
Unit of Experimental Neuro-Oncology, Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy.
Accumulating evidence suggests that only a fraction of neoplastic cells, defined as cancer stem cells (CSC), are responsible for tumor perpetuation. Recent data suggest that neurospheres (NS) from glioblastoma multiforme (GBM) are enriched in CSC. The characterization of this subpopulation of brain tumor cells with a potent tumorigenic activity supports the cancer stem cell hypothesis in solid tumors and may imply that cancer cells are differentially targeted by treatments, including dendritic cell (DC) immunotherapy. To test therapeutic strategies, a good model mimicking the characteristics of GBM-NS and GBM-AC (Adherent Cells) was necessary. One of the most frequently used murine brain tumor models is the GL261 glioma cell line. To see whether GL261 cells could mimic the growth of human GBM-CSC we let them grow in EGF/bFGF without serum. After 5 days neurospheres were visible in the culture medium and were proliferating continuously. The characterization in vivo and in vitro demonstrates that GL261-NS satisfy criteria used to identify CSC and are more immunogenic than AC. DC loaded with GL261-NS lysates protect mice against tumors from both GL261-NS and GL261-AC. Our results suggest that only DC vaccination against neurospheres can restrain the growth of a highly infiltrating and aggressive model of glioma and may have implications for the design of novel, more effective immunotherapy trials for malignant glioma and possibly other malignancies.
PMID: 19582431 [PubMed - in process

<dl class="AbstractPlusReport"><dt class="head">1: J Immunol. 2009 Jun 1;182(11):7287-96.http://www.ncbi.nlm.nih.gov/corehtml...unol_final.gif<script language="JavaScript1.2"><!-- var Menu19454726 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=19454726&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=19454726&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1945 4726&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script> Links

</dt><dd class="abstract">Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes.

<!--AuthorList-->Todaro M, D'Asaro M, Caccamo N, Iovino F, Francipane MG, Meraviglia S, Orlando V, La Mendola C, Gulotta G, Salerno A, Dieli F, Stassi G.
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Colon cancer comprises a small population of cancer stem cells (CSC) that is responsible for tumor maintenance and resistant to cancer therapies, possibly allowing for tumor recapitulation once treatment stops. We previously demonstrated that such chemoresistance is mediated by autocrine production of IL-4 through the up-regulation of antiapoptotic proteins. Several innate and adaptive immune effector cells allow for the recognition and destruction of cancer precursors before they constitute the tumor mass. However, cellular immune-based therapies have not been experimented yet in the population of CSCs. Here, we show that the bisphosphonate zoledronate sensitizes colon CSCs to Vgamma9Vdelta2 T cell cytotoxicity. Proliferation and production of cytokines (TNF-alpha and IFN-gamma) and cytotoxic and apoptotic molecules (TRAIL and granzymes) were also induced after exposure of Vgamma9Vdelta2 T cells to sensitized targets. Vgamma9Vdelta2 T cell cytotoxicity was mediated by the granule exocytosis pathway and was highly dependent on isoprenoid production by of tumor cells. Moreover, CSCs recognition and killing was mainly TCR mediated, whereas NKG2D played a role only when tumor targets expressed several NKG2D ligands. We conclude that intentional activation of Vgamma9Vdelta2 T cells by zoledronate may substantially increase antitumor activities and represent a novel strategy for colon cancer immunotherapy.
</dd></dl>Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1α/VEGF signaling pathways in human breast cancer cells
International Journal of Cancer, 08/12/09
Tang X et al. - In a trial to investigate potential molecular mechanisms underlying the antiangiogenic effect of non-nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, respectively, in insulin-like growth factor (IGF)-1 responsive human breast cancer cells, it was demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1-stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in inhibition of tumor angiogenesis in breast cancer cells.
Methods

• It was tested whether bisphosphonates had any effects on hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) axis that plays a pivotal role in tumor angiogenesis.

Results

• Both pamidronate and clodronate significantly suppressed IGF-1-induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells.
• Mechanistically, either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but they apparently promoted the degradation of IGF-1-induced HIF-1α protein.
• The presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus, indirectly reflecting inhibition of protein synthesis.
• The inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with inhibition of the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways.

http://www.ncbi.nlm.nih.gov/corehtml...nce_150x34.gif <script language="JavaScript1.2"><!-- var Menu19598259 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1959 8259&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.

<!--AuthorList-->Hong SP, Wen J, Bang S, Park S, Song SY.
Division of Gastroenterology, Department of Internal Medicine, Yonsei Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.
Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine-resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC-1 cells. Gemcitabine-resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere-forming activity than parental cells. After high-dose gemcitabine treatment to eliminate most of the cells, CD44(+) cells proliferated and reconstituted the population of resistant cells.ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose-dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. CD44(+)CD24(+)ESA(+) cells remained as a small subset in the resistant cell population. Among ATP-binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44-positive tumors showed poor prognosis. These data indicate that cancer stem-like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer. (c) 2009 UICC.
PMID: 19598259 [PubMed - as supplied by publisher




Reversal of adriamycin resistance by verapamil in human ovarian cancer

<nobr>AM Rogan,</nobr> <nobr>TC Hamilton,</nobr> <nobr>RC Young,</nobr> <nobr>RW Klecker Jr,</nobr> and <nobr>RF Ozols</nobr>
<!-- null -->
The effectiveness of adriamycin in the treatment of ovarian cancer and other human tumors has been limited by the development of drug resistance. Verapamil, a calcium channel blocking agent, completely reversed adriamycin resistance in human ovarian cancer cells with moderate (three- to sixfold) degrees of resistance and partially reversed resistance in highly (150-fold) resistant cells. The potentiating effect of verapamil was due to inhibition of adriamycin efflux in the resistant cells. These results have led to a clinical trial of adriamycin and verapamil in refractory ovarian cancer patients.

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Res. 2008 Jul 15;68(14):5706-15.http://www.ncbi.nlm.nih.gov/corehtml..._full_free.gif <script language="JavaScript1.2"><!-- var Menu18632623 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=18632623&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=18632623&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["Cited in PMC" , "window.top.location='http://www.pubmedcentral.gov/tocrender.fcgi?action=cited&tool=pubmed&pubmedid=1 8632623&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstra ctPlus&ordinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1863 2623&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Temozolomide preferentially depletes cancer stem cells in glioblastoma.

<!--AuthorList-->Beier D, Röhrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Kieslich A, Giebel B, Wischhusen J, Reifenberger G, Hau P, Beier CP.
Department of Neurology, University of Regensburg, Medical School, Regensburg, Germany. Christoph.Beier@gmx.de
The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients.
</dd></dl>

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

Apogenix receives research grants of EUR 2.6 million as part of the Biotechnology Cluster Rhine-Neckar
<!-- ZONE: catid21 --> Heidelberg, July 29th, 2009 - Apogenix GmbH, a biopharmaceutical company developing novel drugs for malignant and inflammatory diseases, today announced that the company has received federal research grants of EUR 2.6 million as one of the companies belonging to the Biotechnology Cluster Rhine-Neckar (BioRN).
In 2008, the BioRN cluster was awarded a total of EUR 40 million as one of the five most important German high-tech regions in the Top Cluster Contest of the German Federal Ministry of Education and Research. The funds will be dedicated to two of Apogenix´ research projects in the field of cancer and inflammatory diseases.
The first program focuses on the development of an IL-4 inhibitor for the treatment of cancer – especially solid tumors which are resistant to chemotherapy and radiation. IL-4 is a cytokine expressed by cancer cells as well as cancer stem cells blocking apoptosis and thereby rendering therapies such as chemotherapy or radiation ineffective. Apogenix´ approach is based on blocking the IL-4 receptor in order to make cancer cells susceptible for treatment. The program will be coordinated by Apogenix and conducted in close collaboration with the research group of Prof Peter Krammer at the German Cancer Research Center (DKFZ).
The second program aims to accelerate the development of inhibitors of the CD95 ligand (CD95L), specifically APG103, for the treatment of chronic inflammatory diseases. CD95 is a receptor inducing apoptosis as well as migration of, e.g. inflammatory cells. Apogenix aims to inhibit CD95 ligand, thereby preventing inflammatory processes right from the start. The research activities to explore the therapeutic potential of APG103 and additional CD95 inhibitors, and to generate preclinical data on these compounds is conducted in collaboration with the research group of Dr Ana Martin-Villalba at the German Cancer Research Center and coordinated by Apogenix. Both programs include activities such as the construction, manufacturing and characterization of novel IL-4 and CD95L inhibitors, as well as pharmacological, pharmacokinetic, safety and mode of action studies. Apogenix´ goal is to advance the most promising IL-4 and CD95L inhibitors to clinical development.
”We are proud about receiving these two research grants,” said Dr Thomas Höger, Chief Executive Officer of Apogenix. “The grants underline the quality and the potential of the research activities of both Apogenix and its collaboration partners at the German Cancer Research Center. With these funds, we hope to accelerate our programs and provide improved treatment options for patients with cancer and chronic inflammatory diseases.”

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

<table width="649" border="0"><tbody><tr><td colspan="7"><table width="649" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td> <table width="649" border="0"><tbody><tr><td colspan="7"><table width="649" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td>Stemline Therapeutics CEO to Present at IBC's New Frontiers in Cancer Drug Development Conference
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</td> </tr> </tbody></table> </td> </tr> <tr> <td> <!-- #BeginEditable "release" --> <!-- Render Story Content --> <table width="649" border="0"> <tbody><tr id="uc_template_trSubHead"> <td colspan="3" style="width: 645px; padding-bottom: 8px;">
</td> </tr> <tr> <td colspan="3" style="width: 645px;"> <link href="http://news.prnewswire.com/StyleSheet.css" type="text/css" rel="stylesheet"><storycontent> NEW YORK, July 30 /PRNewswire/ -- Stemline Therapeutics, Inc., a clinical stage biopharmaceutical company and a leading developer of oncology compounds directed to cancer stem cell targets, today announced that the Company's CEO, Ivan Bergstein M.D. has been invited to present at the New Frontiers in Cancer Drug Development conference which is part of IBC's Drug Discovery and Development Week in Boston, MA. Dr. Bergstein's presentation, entitled "Developing Drug Candidates Directed to Cancer Stem Cell Targets: Preclinical and Clinical Update" is scheduled for 9:50AM on Wednesday August 5(th) at the World Trade Center/Seaport Hotel in Boston. Dr. Bergstein has also been invited to participate in a panel discussion following the presentations.
Cancer stem cell targeted therapeutics have emerged as the next frontier in the fight against cancer. As such, this field is significantly influencing current decision making with respect to oncology drug development. With this in mind, Dr. Bergstein's presentation will cover novel pre-clinical and clinical development paradigms, including human trial design, of drug candidates that target cancer stem cells. The talk will also feature Stemline's latest clinical data, as well as results from its pre-clinical pipeline and drug discovery platforms.
About Stemline Therapeutics, Inc.
Stemline Therapeutics, Inc. is a clinical stage biotechnology company developing novel oncology compounds directed to cancer stem cell targets. Stemline's lead compound, SL-401, targets the interleukin-3 receptor present on multiple hematological cancers including leukemia blasts and leukemia cancer stem cells. SL-401 has demonstrated single agent anti-tumor activity at tolerable doses in a multi-center Phase I human clinical trial. Stemline is also developing a portfolio of biological and small molecule compounds directed at multiple high value cancer stem cell targets of a variety of hematological and solid cancers. Stemline has built a robust discovery platform called "StemScreen(R)" which the Company has utilized to identify multiple compounds that target and impair cancer stem cells. For more information, please visit the Company's website at www.stemline.com.

Stemline Contact: Tom Cirrito, PhD, Director of Operations, Stemline
Therapeutics, Inc. Tel: 212-531-5976; Email: tcirrito@stemline.com
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Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

http://health.usnews.com/articles/he...s-in-mice.html
Compound Targets, Destroys Cancer Stem Cells in Mice

Therapeutic possibilities are uncertain, researchers say

Posted August 13, 2009
THURSDAY, Aug. 13 (HealthDay News) -- Researchers have identified a chemical able to seek out and destroy the stem cells that scientists believe give rise to cancer recurrence after treatment.
A growing body of research is showing that cancer stem cells play a role in cancer metastasis and in causing cancer to reappear even after treatment seems to have eradicated the initial tumor.
"Evidence is accumulating rapidly that cancer stem cells are responsible for the aggressive powers of many tumors," including breast, prostate, lung and others, said study author Robert Weinberg, a member of the Whitehead Institute for Biomedical Research at Massachusetts Institute of Technology.
Yet studying cancer stem cells in the lab has proven problematic. The cells, already fewer in number than other types of tumor cells, tend to lose their stem cell-like properties when grown outside the body.
In the study, which appears in the Aug. 13 online issue of Cell, researchers were able to generate large numbers of cancer cells with stem cell-like qualities through a technique called "epithelial-to-mesenchymal transition," which causes the cells to take on characteristics similar to stem cells.
"A critical aspect of our work was to generate relatively homogenous and stable populations of cancer stem-like cells that could then be used for screening," said co-lead study author Tamer Onder, a former graduate student at the Whitehead Institute for Biomedical Research and now postdoctoral research fellow at Children's Hospital in Boston. "We were able to achieve this by inducing the cancer cells into an epithelial-to-mesenchymal transition using novel reagents that we had developed in the lab."
Researchers then analyzed thousands of chemical compounds to determine which ones were effective in killing breast cancer stem cells.
They found that a chemical called salinomycin destroyed both lab-generated cancer stem cells, as well as naturally occurring ones. When compared to paclitaxel, a common breast cancer chemotherapy drug, salinomycin reduced the number of cancer stem cells by more than 100-fold and inhibited breast tumor regrowth in mice.
Researchers also looked at the effect of salinomycin on genes that previous research has implicated in very aggressive tumors. The study showed salinomycin decreased the activity of these genes, while paclitaxel didn't.
Additional research is needed to determine exactly how salinomycin works to kill cancer stem cells and if it will be as effective in humans as it was in mice, researchers said.


Cancer Advance Identifies Drug to Destroy Powerful Stem Cells
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By Rob Waters
Aug. 14 (Bloomberg) -- Scientists said they have found a drug compound that attacks in a new way the stem cells that fuel tumor growth, opening a path to a new type of anti-cancer treatment.
The compound, salinomycin, reduced the number of cancer stem cells 100 times more than did Bristol-Myers Squibb Co.’s Taxol, a common chemotherapy medicine, according to a report published yesterday in the journal Cell.
The idea that a small group of stem cells drives tumor growth while resisting chemotherapy has been documented by researchers for more than a decade. Scientists at Massachusetts Institute of Technology and the Broad Institute bolstered the theory by showing that the proportion of stem cells in a tumor rose after treatment with standard therapy and declined dramatically with salinomycin.
“It’s exactly the opposite of standard treatment,” said Max Wicha, director of the University of Michigan Comprehensive Cancer Center. “While chemotherapy kills the bulk of cells in a tumor and leaves the cancer stem cells behind, this new treatment does the opposite -- it actually targets and kills the cancer stem cells.”
Wicha, who has developed ways of identifying cancer stem cells, wasn’t involved in yesterday’s study, which he called a “very important” finding.
“This is telling us that cancer stem cells are not going to be resistant to everything,” Wicha said. “It tells us it’s going to be possible to develop specific compounds that can target this cell population.”
New Path to Drugs
The MIT and Broad researchers will conduct further testing of salinomycin in animals to assess its potential to treat humans, said Piyush Gupta, a researcher at the Cambridge, Massachusetts-based Broad Institute and co-author of the study. While the outcome of that research is unknown, the work pinpoints a new way to find effective drugs, he said.
“We now have a method that researchers anywhere in the world can use to find agents that can kill cancer stem cells and potentially treat cancer,” Gupta said yesterday in a telephone interview.
The strategy of finding and attacking these cells results from pioneering work by John Dick, a University of Toronto scientist who in 1997 showed that certain cells in leukemia propelled the growth of new cancer cells. In 2007, he identified similar cells in colon cancer.
Stem cells, for reasons not yet known, appear to fuel the growth of several kinds of cancer including breast, lung and brain tumors, according to studies done in recent years. The cells are resistant to standard cancer therapy, so finding a way to thwart them is important, said Judy Lieberman, a professor of pediatrics at the Immune Disease Institute at Harvard Medical School.
‘These Are the Cells’
“These are the cells that are the important cells and if you don’t eliminate them, the tumors can grow back and recur,” Lieberman said yesterday in a telephone interview. “Any way you can figure out to specifically target the cancer stem cells is going to fill an important gap in the therapies we have at hand.”
Scientists at universities and biotechnology companies including Infinity Pharmaceuticals Inc. of Cambridge, Massachusetts, and Australia’s ChemGenex Pharmaceuticals Ltd. are working to develop treatments to block the stem cells. Findings released in 2007 showed that one marketed anti-cancer drug, GlaxoSmithKline’s Tykerb, reduced the number of cancer stem cells and helped eliminate the disease in some breast cancer patients.
Tumor-Initiating Cells
Research by Jenny Chang at the Baylor College of Medicine has shown that after breast-cancer patients got chemotherapy or hormone treatments, the remaining malignancy had a greater percentage of tumor-initiating cells than before.
The MIT and Broad researchers grew cancer cells from breast tumors in a way that increased the number of stem cells. They then used rapid screening techniques to test 16,000 commercially available chemical compounds. They identified 32 candidates before settling on salinomycin as the most potent.
They tested the compound in mice in two ways. First, they exposed breast cancer stem cells in laboratory dishes to salinomycin and Taxol and tallied how many cells they would need to inject in a mouse to trigger a tumor. It took many more of the salinomycin-treated cells to spur cancer, showing that the compound was inhibiting cancer development, Gupta said.
Second, they induced tumors in mice and treated them with the two drugs. While both drugs exerted “significant anti-tumor effects,” the mice treated with Taxol had a greater proportion of cancer stem cells left in the remaining tumor. Taxol enriched the population of cancer stem cells and salinomycin reduced it, Gupta said.
“We have now a systematic way to look for compounds that selectively kill cancer stem cells,” Gupta said. “We’ve taken a lot of the serendipity out of the equation.”
The research was funded partly by the National Cancer Institute.
To contact the reporter on this story: Rob Waters in San Francisco at rwaters5@bloomberg.net.
Last Updated: August 14, 2009 00:01 EDT

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.

<!--AuthorList-->Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
The ATP-binding cassette (ABC) transporters (ABC-T) actively efflux structurally and mechanistically unrelated anticancer drugs from cells. As a consequence, they can confer multidrug resistance (MDR) to cancer cells. ABC-T are also reported to be phenotypic markers and functional regulators of cancer stem/initiating cells (CSC) and believed to be associated with tumor initiation, progression, and relapse. Dofequidar fumarate, an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both. Phase III clinical trials suggested that dofequidar had efficacy in patients who had not received prior therapy. Here we show that dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction. Estimation of ABC-T expression revealed that ABCG2/breast cancer resistance protein (BCRP) mRNA level, but not the ABCB1/P-gp or ABCC1/MDR-associated protein 1 mRNA level, in all the tested SP cells was higher than that in non-SP cells. The in vitro vesicle transporter assay clarified that dofequidar had the ability to suppress ABCG2/BCRP function. Dofequidar treatment sensitized SP cells to anticancer agents in vitro. We compared the antitumor efficacy of irinotecan (CPT-11) alone with that of CPT-11 plus dofequidar in xenografted SP cells. Although xenografted SP tumors showed resistance to CPT-11, treatment with CPT-11 plus dofequidar greatly reduced the SP-derived tumor growth in vivo. Our results suggest the possibility of selective eradication of CSC by inhibiting ABCG2/BCRP. (Cancer Sci 2009).
PMID: 19673889 [PubMed - as supplied by publisher]

The mentioned previous study:
http://jco.ascopubs.org/cgi/content/abstract/25/4/411

Results ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF,a 24.6% relative improvement and 10.5% absolute increase (P= .077). There was a trend for prolonged progression-free survival(PFS; median 241 days for CAF v 366 days for dofequidar + CAF;P = .145). In retrospectively defined subgroups, significantimprovement in PFS in favor of dofequidar was observed in patientswho were premenopausal, had no prior therapy, and were stageIV at diagnosis with an intact primary tumor. Except for neutropeniaand leukopenia, there was no statistically significant excessof grade 3/4 adverse events compared with CAF. Treatment withdofequidar did not affect the plasma concentration of doxorubicin.
Conclusion Dofequidar + CAF was well tolerated and is suggested to haveefficacy in patients who had not received prior therapy.
<!-- FN --> <!-- null --> published online ahead of print at www.jco.org on December 18,2006.
Supported by Schering AG, Berlin, Germany.
Presented in part at the 29th European Society for Medical OncologyCongress, Vienna, Austria, October 29–November 2, 2004,and the 27th San Antonio Breast Cancer Conference, San Antonio,TX, December 8-11, 2004.

cyclopamine, cyclopamine plus Rapamycin
 

http://www.eurekalert.org/pub_releas...w-pm082409.php

'Hedgehog' pathway may hold key to anti-cancer therapy

Research into the role of pathway gene could provide novel method to treat cancer metastases

Scientists in Switzerland have discovered a way to block the growth of human colon cancer cells, preventing the disease from reaching advanced stages and the development of liver metastases. The research, published today in EMBO Molecular Medicine, shows that blocking the so-called Hedgehog-GLI pathway can prevent the growth of tumours, metastatic lesions and cancer stem cells, the cells thought to lie at the root of cancer growth.
Colon cancer often begins in a treatable form when it is confined to the bowel wall, but in frequent cases it can develop to an incurable metastatic stage. A Geneva-based research team has discovered the essential role played by HH-GLI in the progression of colon cancer to these late and incurable stages. HH-GLI is a signalling pathway used by cells to communicate with each other, often used to determine position, growth and survival.
"Previous works hinted at the possible role of HH-GLI in colon cancer, but this was denied by other studies, so its involvement was never entirely clear," said lead researcher Professor Ariel Ruiz i Altaba of Geneva University. "In this study we have proven that HH-GLI is essential for the development and growth of colon cancers. The research demonstrates the active presence of HH-GLI signalling in epithelial cells of colon cancers. Moreover, we find that metastatic tumours rely on this pathway for sustained growth. This identifies HH-GLI as a target for novel anti-cancer therapies against so far incurable forms of colon cancer in distant organs, such as the liver."
This research opens the possibility of new anti-cancer therapies, specifically the use of RNA interference and of Cyclopamine, a plant product known to block Hedgehog pathway activity. This and other similar molecules can now be considered for future research as a treatment for terminal patients with metastatic disease and to fight resurgent forms of the disease.
"Recurrence is a major problem in cancer treatment. Even after a patient has displayed an apparent complete recovery from a primary tumour, recurrence at nearby or distal locations has a poor prognosis," said Ruiz i Altaba. "While monitoring recovering mice we noted that tumours began to recur in all cases except for those treated with Cyclopamine for a short period of time after tumour disappearance. The treated mice were kept for up to one year after the treatment and remained healthy and tumour free."
Using these genetic or pharmacologic methods to block HH-GLI activity also prevents cancer stem cell self-renewal. Using a new in vivo assay to test the participation of cancer stem cells in a growing tumour, the research team demonstrated the essential role of this pathway for the maintenance and survival of cancer stem cells.
"This work firmly establishes the critical action of HH-GLI in human colon cancer cells, providing the platform for preclinical and future clinical work." concluded Ruiz i Altaba. "The finding that a blockade of HH-GLI for a relatively short period was sufficient to eliminate the tumour and prevent recurrence, without negatively affecting the health of the mice, opens the possibility for the use of a therapeutic window to eradicate the tumour without major side effects."

Contact: Ben Norman
Benorman@wiley.com
44-124-377-0375
Wiley-Blackwell


Oncogene (<abbr class="published" title="2009-11-23">23 November 2009</abbr>) | <abbr title="Digital Object Identifier">doi</abbr>:10.1038/onc.2009.392
<!--COinS--> Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

L Yang , G Xie , Q Fan & J Xie
Abstract

The hedgehog pathway, initially discovered by two Nobel laureates Drs E Wieschaus and C Nusslein-Volhard in Drosophila, is a major regulator for cell differentiation, tissue polarity and cell proliferation. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas (BCCs), medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last 2 years in our understanding of hedgehog signaling activation in human cancer, interactions between hedgehog signaling and other pathways in carcinogenesis, potential antagonists for hedgehog signaling inhibition and their clinical implications for human cancer treatment. Oncogene advance online publication, 23 November 2009; doi:10.1038/onc.2009.392




Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer.

<!--AuthorList-->Mueller MT, Hermann PC, Witthauer J, Rubio-Viqueira B, Leicht SF, Huber S, Ellwart JW, Mustafa M, Bartenstein P, D'Haese JG, Schoenberg MH, Berger F, Hidalgo M, Heeschen C.
Experimental Medicine, Department of Surgery, Ludwig-Maximilian-University, Munich, Germany.
BACKGROUND & AIMS: Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. METHODS: We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. RESULTS: Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. CONCLUSIONS: The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.



August 31, 2000
<!-- Headline --> Plant Compound Blocks Action of Cancer Genes
http://www.hhmi.org/news/beachy.html

http://www.hhmi.org/research/investigators/beachy.html
Hedgehog Signaling in Development and Disease

1: J Med Chem. 2009 Jul 23;52(14):4400-18.http://www.ncbi.nlm.nih.gov/corehtml...es-acspubs.jpg<script language="JavaScript1.2"><!-- var Menu19522463 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=19522463&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1952 2463&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script> Links

<dd class="abstract">
Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

<!--AuthorList-->Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC, Yu LC, Behnke ML, Nair SJ, Hagel M, White K, Conley J, Manna JD, Alvarez-Diez TM, Hoyt J, Woodward CN, Sydor JR, Pink M, MacDougall J, Campbell MJ, Cushing J, Ferguson J, Curtis MS, McGovern K, Read MA, Palombella VJ, Adams J, Castro AC.
Infinity Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA. Martin.Tremblay@infi.com
Recent evidence suggests that blocking aberrant hedgehog pathway signaling may be a promising therapeutic strategy for the treatment of several types of cancer. Cyclopamine, a plant Veratrum alkaloid, is a natural product antagonist of the hedgehog pathway. In a previous report, a seven-membered D-ring semisynthetic analogue of cyclopamine, IPI-269609 (2), was shown to have greater acid stability and better aqueous solubility compared to cyclopamine. Further modifications of the A-ring system generated three series of analogues with improved potency and/or solubility. Lead compounds from each series were characterized in vitro and evaluated in vivo for biological activity and pharmacokinetic properties. These studies led to the discovery of IPI-926 (compound 28), a novel semisynthetic cyclopamine analogue with substantially improved pharmaceutical properties and potency and a favorable pharmacokinetic profile relative to cyclopamine and compound 2. As a result, complete tumor regression was observed in a Hh-dependent medulloblastoma allograft model after daily oral administration of 40 mg/kg of compound 28.
</dd><dd class="abstract">
</dd><dd class="abstract">
</dd><dd class="abstract">PMID: 19522463 [PubMed - indexed for MEDLINE </dd>



Discussion of how to get Cyclopamine and anecdotal patient success:
http://margaret.healthblogs.org/2008...n-cyclopamine/


Since Cyclopamine, though available, is an investigational substance, the natural alternatives:



Mol Carcinog. 2009 Dec 18. [Epub ahead of print]
Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells.

Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A, Aboussekhra A.
Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Medulloblastoma is an aggressive primary brain tumor that arises in the cerebellum of children and young adults. The Sonic Hedgehog (Shh) signaling pathway that plays important roles in the pathology of this aggressive disease is a promising therapeutic target. In the present report we have shown that curcumin has cytotoxic effects on medulloblastoma cells. Curcumin suppressed also cell proliferation and triggered cell-cycle arrest at G(2)/M phase. Moreover, curcumin inhibited the Shh-Gli1 signaling pathway by downregulating the Shh protein and its most important downstream targets GLI1 and PTCH1. Furthermore, curcumin reduced the levels of beta-catenin, the activate/phosphorylated form of Akt and NF-kappaB, which led to downregulating the three common key effectors, namely C-myc, N-myc, and Cyclin D1. Consequently, apoptosis was triggered by curcumin through the mitochondrial pathway via downregulation of Bcl-2, a downstream anti-apoptotic effector of the Shh signaling. Importantly, the resistant cells that exhibited no decrease in the levels of Shh and Bcl-2, were sensitized to curcumin by the addition of the Shh antogonist, cyclopamine. Furthermore, we have shown that curcumin enhances the killing efficiency of nontoxic doses of cisplatin and gamma-rays. In addition, we present clear evidence that piperine, an enhancer of curcumin bioavailability in humans, potentiates the apoptotic effect of curcumin against medulloblastoma cells. This effect was mediated through strong downregulation of Bcl-2. These results indicate that curcumin, a natural nontoxic compound, represents great promise as Shh-targeted therapy for medulloblastomas. (c) 2009 Wiley-Liss, Inc.

PMID: 20025076 [PubMed - as supplied by publisher]


http://www.faqs.org/patents/app/20090054517
Patent application title: Phytoestrogens As Regulators Of Hedgehog Signaling And Methods Of Their Use In Cancer Treatment
Abstract: A new method is provided for inhibiting tumor growth and for delaying the onset of cancer. Several estrogenic compounds from plants are capable of inhibiting cell proliferation both in cell cultures and in whole animals. These compounds likely exert their anti-proliferation effects by inhibiting the Hedgehog signaling pathway. Estrogen receptors may also play an essential role in the inhibitory effect of these compounds.




Chembiochem. 2008 May 5;9(7):1082-92.
Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription.
http://www3.interscience.wiley.com/j...45574/abstract

Hosoya T, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M.
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystaurosporinone (10), arcyriaflavin C (11) and 5,6-dihydroxyarcyriaflavin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physalins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis Bcl2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.

PMID: 18357592 [PubMed - indexed for MEDLINE]


<table width="100%"><tbody><tr><td>High content of zerumbone in volatile oils of Zingiber zerumbet from southern India and Malaysia

http://www3.interscience.wiley.com/j...17925/abstract
</td></tr><tr><td>Sabulal Baby^{1 *}, Mathew Dan², Abdul R. M. Thaha², Anil J. Johnson¹, Rajani Kurup¹, Prasanth Balakrishnapillai¹, Chong Keat Lim³</td></tr><tr><td>¹Phytochemistry and Phytopharmacology Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India
²Plant Genetic Resources Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India
³Folia Malaysiana, 215 Macalister Road, 10450 Penang, Malaysia
</td></tr><tr><td>email: Sabulal Baby (sabulal@gmail.com)</td></tr></tbody></table>^*Correspondence to Sabulal Baby, Phytochemistry and Phytopharmacology Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India

Abstract<table border="0" width="100%"><tbody><tr><td>Zerumbone is a sesquiterpene phytochemical with potential anticancer, anti-inflammatory, anti-HIV and other biological activities, most abundantly found in Zingiber zerumbet (L.) Smith. Previous studies reported 12.6-73.1% of zerumbone in Z. zerumbet rhizome oils from various geographical locations. In a careful review of the literature, we found that most of the previous gas chromatographic profiling studies on volatile oils of Z. zerumbet were inadequate, since they were based on poor identification and quantification procedures and also on single-sample data. In this study, we report the chemical profiles of volatile oils of Z. zerumbet rhizomes from six locations in the southern Indian state of Kerala and also from Penang in Malaysia. Chemical profiling of volatiles was carried out by extensive GC-FID, GC-MS and associated techniques, supported by ¹H-NMR, ¹³C-NMR, FABMS and HPTLC. The full chemical profiles of rhizome oils of these seven accessions of Z. zerumbet were elucidated. The south Indian accessions of Z. zerumbet reported 76.3-84.8% zerumbone content in their rhizome oils. The Malaysian accession recorded the lowest content of zerumbone (68.9%). This study reveals the high content of the bioactive compound zerumbone in Z. zerumbet from Kerala. Copyright © 2009 John Wiley & Sons, Ltd.</td></tr></tbody></table><hr align="left" size="1" width="25%">Received: 3 February 2009; Revised: 9 June 2009; Accepted: 12 June 2009

Zerumbone possibly better, discussed:
http://margaret.healthblogs.org/2008...bone/#comments

Cyclopamine and Zerumbone sourced and informally trialed here:
http://www.curingourselves.com/


Evid Based Complement Alternat Med. 2009 Jun 18. [Epub ahead of print]
Cytotoxic Activities of Physalis minima L. Chloroform Extract on Human Lung Adenocarcinoma NCI-H23 Cell Lines by Induction of Apoptosis.

http://ecam.oxfordjournals.org/cgi/content/full/nep057v1


Leong OK, Muhammad TS, Sulaiman SF.
School of Biological Sciences, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. shaida@usm.my.
Physalis minima L. is reputed for having anticancer property. In this study, the chloroform extract of this plant exhibited remarkable cytotoxic activities on NCI-H23 (human lung adenocarcinoma) cell line at dose- and time-dependent manners (after 24, 48 and 72 h of incubation). Analysis of cell-death mechanism demonstrated that the extract exerted apoptotic programed cell death in NCI-H23 cells with typical DNA fragmentation, which is a biochemical hallmark of apoptosis. Morphological observation using transmission electron microscope (TEM) also displayed apoptotic characteristics in the treated cells, including clumping and margination of chromatins, followed by convolution of the nuclear and budding of the cells to produce membrane-bound apoptotic bodies. Different stages of apoptotic programed cell death as well as phosphatidylserine externalization were confirmed using annexin V and propidium iodide staining. Furthermore, acute exposure to the extract produced a significant regulation of c-myc, caspase-3 and p53 mRNA expression in this cell line. Due to its apoptotic effect on NCI-H23 cells, it is strongly suggested that the extract could be further developed as an anticancer drug.

PMID: 19541726 [PubMed - as supplied by publisher]

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

: Expert Opin Drug Metab Toxicol. 2009 Aug 27. [Epub ahead of print]

<dd class="abstract">
ABCG2: the key to chemoresistance in cancer stem cells?

<!--AuthorList-->An Y, Ongkeko WM.
Stanford University School of Medicine, Stanford, CA 94305.
Multi-drug chemoresistance remains one of the most common reasons for chemotherapy failure. The membrane transporter protein ABCG2/BCRP1 has been shown in vitro to effectively reduce the intracellular concentrations of several prominent anticancer chemotherapeutic agents such as mitoxantrone and doxorubicin. Intriguingly, cancer stem cells are known to be characterized by multi-drug chemoresistance. Taking into account that the ABCG2(+) subset of tumor cells are often enriched with cells with cancer stem-like phenotypes, it has been proposed that ABCG2 activity underlies the ability of cancer cells to regenerate post-chemotherapy. Furthermore, we also review evidence suggesting that tyrosine kinase inhibitors, including imatinib and gefitinib, are both direct and downstream inactivators of ABCG2 and, therefore, serve as candidates to reverse cancer stem cell chemoresistance and potentially target cancer stem cells.

<table style="border: 1px solid rgb(0, 0, 0); width: 632px; height: 787px;" width="632" border="0" cellpadding="3" cellspacing="0"><tbody><tr><td>http://www.medicalnewstoday.com/articles/165763.php</td></tr><tr><td>10/1/09 Less toxic alternative to Imatinib</td></tr><tr><td><table width="100%" border="0" cellpadding="5" cellspacing="0"><tbody><tr><td valign="top"> </td></tr></tbody></table></td></tr></tbody></table>
Leuk Res. 2006 Oct;30(10):1249-52. Epub 2006 Mar 31.
Addition of sargramostim (GM-CSF) to imatinib results in major cytogenetic response in a patient with chronic myeloid leukemia.

Connor RF, Hurd D, Pettenati MJ, Koty P, Molnár I.
Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. rconnor@wfubmc.edu
Imatinib mesylate, an inhibitor of BCR/ABL tyrosine kinase, has remarkable activity in chronic myeloid leukemia resulting in an 87% major cytogenetic response. We describe a woman who failed to achieve any cytogenetic response after 2.5 years of imatinib, 400mg daily. When daily sargramostim (GM-CSF) 100 microg/m2 was added, cytogenetic studies revealed a gradual increase in percentage of normal cells from start, 4, 9, and 15 months at 0%, 10%, 55%, and 85%, respectively. She became transfusion independent after starting GM-CSF. The addition of GM-CSF to imatinib resulted in a clinical benefit and a major cytogenetic response in this patient.

PMID: 16580068 [PubMed - indexed for MEDLINE]

</dd>

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

<dl class="AbstractPlusReport"><dt class="head">1: J Control Release. 2008 Jul 2;129(1):18-25. Epub 2008 Apr 4.http://www.ncbi.nlm.nih.gov/corehtml...PubMedLink.gif<script language="JavaScript1.2"><!-- var Menu18466993 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=18466993&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=18466993&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1846 6993&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script> Links

</dt><dd class="abstract">A potential target associated with both cancer and cancer stem cells: a combination therapy for eradication of breast cancer using vinorelbine stealthy liposomes plus parthenolide stealthy liposomes.

<!--AuthorList-->Liu Y, Lu WL, Guo J, Du J, Li T, Wu JW, Wang GL, Wang JC, Zhang X, Zhang Q.
State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
The cancer stem cells play a critical role in both initiation and relapse of the cancers as they are resistant to the most of cytotoxic agents and able to proliferate indefinitely. Vinorelbine stealthy liposomes and parthenolide stealthy liposomes were developed for providing beneficial pharmacological properties and to eradicate cancer stem cells and non-stem cancer cells together by a combination therapy. Cytotoxicity and cancer stem-like cells (side population, SP) identification were performed on human breast cancer cell lines MCF-7 and MDA-MB-231. SP cells were further sorted from MCF-7 cells and characterized. Inhibitory effect was evaluated on the sorted SP and non-SP cells. Antitumor activity was evaluated on MCF-7 xenografts in nude mice. SP cells were identified with a higher percentage in MCF-7 cells (3.8%) and lower in MDA-MB-231 cells (0.6%). Both vinorelbine and parthenolide inhibited the proliferation in MCF-7 and MDA-MB-231 cells. As compared to non-SP cells, inhibitory effect of vinorelbine in the SP cells was lower while a robust inhibitory effect was observed when applying vinorelbine in combination with parthenolide. In the MCF-7 xenografts, stealthy liposomal vinorelbine plus stealthy liposomal parthenolide produced a full inhibitory effect. This combination therapy may provide a potential strategy for eradication of breast cancer by targeting cancer together with cancer stem cells.
PMID: 18466993 [PubMed - indexed for MEDLINE]

</dd></dl>

<dl class="AbstractPlusReport"><dt class="head">1: Breast Cancer Res Treat. 2008 Oct;111(3):419-27. Epub 2007 Oct 27.http://www.ncbi.nlm.nih.gov/corehtml...ringerlink.gif<script language="JavaScript1.2"><!-- var Menu17965935 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=17965935&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=17965935&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1796 5935&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script> Links

</dt><dd class="abstract">NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells.

<!--AuthorList-->Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y.
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Accumulating evidence indicates that breast cancer is caused by cancer stem cells and cure of breast cancer requires eradication of breast cancer stem cells. Previous studies with leukemia stem cells have shown that NF-kappaB pathway is important for leukemia stem cell survival. In this study, by using MCF7 sphere cells as model of breast cancer stem-like cells, we evaluated the effect of NF-kappaB pathway specific inhibitors on human breast cancer MCF7 sphere cells.cells known to enrich in breast cancer stem-like cells. The preferential inhibition effec Three inhibitors including parthenolide (PTL), pyrrolidinedithiocarbamate (PDTC) and its analog diethyldithiocarbamate (DETC) were found to preferentially inhibit MCF7 sphere cell proliferation. These compounds also showed preferential inhibition in term of proliferation and colony formation on MCF7 side population (SP) cells, a small fraction of MCF7 t of these compounds was due to inhibition of the NF-kappaB activity in both MCF7 sphere and MCF7 cells, with higher inhibition effect on MCF7 sphere cells than on MCF7 cells. PDTC was further evaluated in vivo and showed significant tumor growth inhibition alone but had better tumor growth inhibition in combination with paclitaxel in the mouse xenograft model than either PDTC or paclitaxel alone. This study suggests that breast cancer stem-like cells could be selectively inhibited by targeting signaling pathways important for breast cancer stem-like cells.
PMID: 17965935 [PubMed - indexed for MEDLINE
</dd></dl>
Oncogene (2004) 23, 7330–7344. doi:10.1038/sj.onc.1207995 Published online 2 August 2004
Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

Harikrishna Nakshatri^1,2,3,4, Susan E Rice⁵ and Poornima Bhat-Nakshatri^3,4

1. ¹Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2. ²Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3. ³Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
4. ⁴Walther Cancer Institute, Indianapolis, IN 46208, USA
5. ⁵Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

Correspondence: H Nakshatri, R4-202, Indiana Cancer Research Institute, 1044 West Walnut St., Indianapolis, IN 46202, USA. E-mail: hnakshat@iupui.edu
Received 4 May 2004; Revised 25 June 2004; Accepted 27 June 2004; Published online 2 August 2004.

Top of pageAbstract

The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-http://www.nature.com/__chars/kappa/...base/glyph.gifB and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-http://www.nature.com/__chars/kappa/...base/glyph.gifB DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c but not Smac/DIABLO was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves 'feed forward' activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.
Keywords:

parthenolide, TRAIL, apoptosis, JNK, NF-http://www.nature.com/__chars/kappa/...base/glyph.gifB, breast cancer

Abbreviations:

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; JNK, c-Jun N-terminal kinase; PARP, poly(ADP-ribose) polymerase; Z-VAD-FMK, N-tert-butoxy-carbonyl-Val-Ala-Asp-fluromethyl-ketone; NF-http://www.nature.com/__chars/kappa/...base/glyph.gifB, nuclear factor kappaB; EMSA, electrophoretic mobility shift assay; XIAP, X-linked inhibitor of apoptosis protein; Smac, second mitochondria-derived activator of caspases; MTS, (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

Microtubule-interfering activity of parthenolide.
Chem Biol Interact. 2004 Oct 15;149(2-3):165-73.
Parthenolide is an active sesquiterpene lactone present in a variety of medicinal herbs (feverfew), well known as anti-inflammatory drug. It has recently been proposed as a chemotherapeutic drug, but the pharmacological pathways of its action have not yet been fully elucidated. Firstly, we explored whether the anticancer properties of parthenolide may be related to a tubulin/microtubule-interfering activity. We additionally compared bioactivities of parthenolide with those checked after combined treatments with paclitaxel in human breast cancer MCF-7 cells. Parthenolide exerted in vitro stimulatory activity on tubulin assembly, by inducing the formation of well-organized microtubule polymers. Light microscopy detections showed that parthenolide-induced alterations of either microtubule network and nuclear morphology happened only after combined exposures to paclitaxel. In addition, the growth of MCF-7 cells was significantly inhibited by parthenolide, which enhanced paclitaxel effectiveness. In conclusion, the antimicrotubular and antiproliferative effects of parthenolide, well known microtubule-stabilizing anticancer agent, may influence paclitaxel activity. The tubulin/microtubule system may represent a novel molecular target for parthenolide, to be utilized in developing new combinational anticancer strategies.

1: Prostate. 2009 Jun 1;69(8):827-37. <script language="JavaScript1.2"><!-- var Menu19204913 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["Compound (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pccompound&DbFrom=pubmed&Cmd=Link&LinkNa me=pubmed_pccompound_mesh&LinkReadableName=Compoun d%20(MeSH%20Keyword)&IdsFromResult=19204913&ordina lpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_R esultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstrac tPlus' ", "", ""], ["References for this PMC Article" , "window.top.location='/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=p ubmed_pubmed_refs&LinkReadableName=References%20fo r%20this%20PMC%20Article&IdsFromResult=19204913&or dinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubm ed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbs tractPlus' ", "", ""], ["Substance (MeSH Keyword)" , "window.top.location='/sites/entrez?Db=pcsubstance&DbFrom=pubmed&Cmd=Link&LinkN ame=pubmed_pcsubstance_mesh&LinkReadableName=Subst ance%20(MeSH%20Keyword)&IdsFromResult=19204913&ord inalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubme d_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbst ractPlus' ", "", ""], ["Free in PMC" , "window.top.location='http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=19204913&i tool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPa nel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus&or dinalpos=1' ", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1920 4913&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
<dd class="abstract">
Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach.

<!--AuthorList-->Kawasaki BT, Hurt EM, Kalathur M, Duhagon MA, Milner JA, Kim YS, Farrar WL.
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick (NCI-Frederick), National Institutes of Health,1050Boyles Street, Frederick, MD 21702, USA.
Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1. (XBP1), and p53 In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment. (c) 2009 Wiley-Liss, Inc.
PMID: 19204913 [PubMed - indexed for MEDLINE
</dd>

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

GENova files patent for new breast cancer treatment

Thu Sep 10, 2009 6:01am EDT

NEW YORK, NY, Sept. 10 /PRNewswire-FirstCall/ - (OTCBB: GVBP.OB) - GENova
Biotherapeutics, Inc., ("GENova"), a biotechnology company that identifies,
acquires, and develops novel drug targets that disrupt the advance of
life-threatening diseases, today announced it has filed a patent for a
potential blockbuster drug target that combats breast cancer.
The target, Tetanolic acid, is a tailor-made lipid which induces cell death in
breast cancer cells, thus curtailing development of the harmful cancer.
This novel approach - using proteins to stop cancer - is based on recent
discoveries that indicate that most tumors are derived from a cancer stem
cell. The technology behind Tetanolic acid involved identifying specific
characteristics of these cancer stem cells and then tailoring a lipid
(Tetanolic acid) that can identify these characteristics and then attack the
malignant cells whilst leaving healthy cells intact. This tailor-made cancer
treatment strategy is far superior to any existing therapies, as it terminates
the cancer at the source, with no side effects, and no harm to surrounding
healthy tissues.
"This target has tremendous market potential, as it can ultimately eliminate
the need for surgery and chemotherapy," says Aaron Whiteman for GENova.
Worldwide, breast cancer is the fifth most common cause of cancer death, and
is the most common cancer (and cause of cancer death) in women. The demand for
new and better treatments for the disease is as urgent as ever.
Whiteman explains GENova's novel approach: "If you compared this disease to a
tree, so far, treatments have only treated the crown of the tree - its
branches and leaves, and even tried to hit the stem, but no treatment has
penetrated its roots. Now that we can identify cancer stem cells, we can
remove the root at its formation, and therefore eliminate all sources of life
to the tumor. That is the potential behind Tetonolic acid."


http://www.genovabio.com/pipeline.html
Tetanolic acid: Promising novel lipid molecule for breast cancer
Known as an alpha hydroxyoleic acid, tetanolic acid is a form of a lipid which is also found as a main component of olive oil. Alpha hydroxyoleic acids are able to interact with the cell membrane in order to control its composition or structure with affect on the receptors on the membrane. This control mechanism affects the growth and proliferation of cells – and seeing that cancer is characterised as a normal proliferation of cells, these lipids can potentially prevent cancer spread (Ohba et al., 2007 Int. J. Cancer 121 (1)).
Tests have been shown that such analogues of oleic acid are able to prevent the growth and spread of cancers, including breast cancer, in mice. That is why GENova's Tetanolic acid is a candidate for development of an anti-cancer medicament in humans.




Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13754-8. Epub 2009 Aug 3.
Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid.

Lladó V, Terés S, Higuera M, Alvarez R, Noguera-Salva MA, Halver JE, Escribá PV, Busquets X.
Laboratory of Cell Biology and Laboratory of Molecular Cell Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain.
alpha-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.

PMID: 19666584 [PubMed - indexed for MEDLINE]

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

Diabetes drug also kills cancer stem cells
BOSTON, Sept. 14 (UPI) -- U.S. scientists say they've found that in human breast cancer cell tumors in mice, a diabetes drug worked better than chemotherapy in prolonging remission.
Researchers led by Harvard Medical School Professor Kevin Struhl said the mice appeared tumor-free for two months after treatment before the end of the experiment. The drug, metformin, appears to selectively kill cancer stem cells in culture dishes and in mice.
The scientists said their findings provide additional rationale for testing metformin in combination with chemotherapy in people with breast cancer and perhaps other cancers.
The scientists said their findings add to a growing body of preliminary evidence in cells, mice, and people that metformin may improve breast cancer outcomes in people. In the new study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes, the researchers said.
The study that included Heather Hirsch and Dimitrios Iliopoulos, along with Dr. Philip Tsichlis of Tufts University Medical Center, is reported in the early online edition of the journal Cancer Research.




Combo with anti-diabetes drug found effective against cancer
(AFP) – Sept. 14
SAN FRANCISCO — An anti-diabetes drug reduced tumors faster and prolonged remission further than chemotherapy when tested on mice, apparently by targeting cancer stem cells, a new report by Harvard Medical School found.
The report, published Monday in the online journal Cancer Research, argued that the drug metformin may improve breast cancer outcomes in people.
"We have found a compound selective for cancer stem cells," said senior author Kevin Struhl, a professor of biological chemistry and molecular pharmacology at Harvard Medical School. "What's different is that ours is a first-line diabetes drug."
In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.
The combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture, the report said. The researchers used four genetically distinct breast cancer cell lines.
In mice, pretreatment with the diabetes drug prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors.
In other mice where tumors were allowed to take hold for 10 days, the dual therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone, accordign to the study.
In the two months between the end of treatment and the end of the experiment, tumors regrew in mice treated with chemotherapy alone, but not in mice that had received both drugs.
By itself, metformin was ineffective in treating tumors.
"There is a big desire to find drugs specific to cancer stem cells," Struhl explained.
"The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already used as a first-line diabetes drug."


Diabetes drug kept breast tumors away in mice

Mon Sep 14, 2009 7:45pm BST
By Julie Steenhuysen
CHICAGO (Reuters) - Adding the common diabetes drug metformin to chemotherapy helped shrink breast cancer tumors faster in mice and keep them away longer than chemotherapy alone, raising hope for a more effective way to treat cancer, U.S. researchers said on Monday.
They said metformin appeared to target breast cancer stem cells -- a kind of master cancer cell that resists conventional treatment and may be the source of many tumors that grow back.
"What's exciting here is we now have something that is mechanistically a different kind of killer of cancer that can synergize with chemotherapy," Kevin Struhl of Harvard Medical School, whose study appears in the journal Cancer Research, said in a telephone briefing.
Many teams have been looking for ways to destroy the master cancer cells in the hope of making cancer easier to cure.
Last month, a team at the Broad Institute of Harvard and the Massachusetts Institute of Technology reported that a chemical called salinomycin could kill breast cancer stem cells.
What is different with his study, Struhl said, is that metformin is a widely used drug with a long safety track record. "There are tens of millions of people who take this drug," he said.
"Although our studies are limited to mice and cells, metformin has a history of anti-cancer effects," he said.
Metformin has already been shown to reduce the risk of some cancers, including pancreatic and breast cancer, in large studies of people with diabetes.
Struhl said metformin's affect on cancer stem cells appeared to be separate from its ability to help the body use insulin and lower blood sugar -- which also can improve breast cancer survival.
His team studied metformin and the cancer drug doxorubicin in lab dishes and found they killed both human cancer stem cells and non-stem cancer cells.
Mice that had tumors and got metformin and chemotherapy were less likely to have tumors grow back two months after treatment compared with mice that got chemotherapy alone.
"When we had both drugs together, we lost the tumors faster, but more importantly, there was no relapse," Struhl said.
He said with metformin, it may be possible to reduce the chemotherapy dose and still get the same benefit.
That will need to be studied in people and a study is getting under way. Dr. Jennifer Ligibel, at Dana-Farber Cancer Institute and Harvard, is organizing a large trial with colleagues in Canada to study metformin in women with early stage breast cancer.

<dl class="AbstractPlusReport"><dt class="head">1: Cancer Res. 2009 Sep 14. [Epub ahead of print]http://www.ncbi.nlm.nih.gov/corehtml...anres_full.gif <script language="JavaScript1.2"><!-- var Menu19752085 = [ ["UseLocalConfig", "jsmenu3Config", "", ""], ["LinkOut", "window.top.location='/sites/entrez?Cmd=ShowLinkOut&Db=pubmed&TermToSearch=1975 2085&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubm ed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubme d_RVAbstractPlus' ", "", ""] ] --></script>Links
</dt><dd class="abstract"> Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission.
</dd><dd class="abstract">
</dd><dd class="abstract">link to FULL TEXT
<!--AuthorList--></dd><dd class="abstract">
</dd><dd class="abstract">Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts.
The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non-stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2 months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):OF1-5].</dd></dl>
http://www.pharmacorama.com/en/Sections/Insulin_4.php

Enhancers of insulin effects, metformin

The drugs which potentiate the effects of insulin are metformin and thiazolidinediones derivatives.
Metformin is a biguanide. It decreases hyperglycemia without risk of hypoglycemia because it does not lower glycemia in healthy subjects. It has an antihyperglycemic effect. Contrary to sulfonylureas, metformin does not stimulate insulin secretion. It can thus be regarded as a potentialisator of insulin.
Its mechanism of action is complex. It acts in the presence of insulin:

• by increasing glucose uptake and utilization by tissues, in particular by skeletal muscles
• by decreasing hepatic glucose production: it decreases hepatic gluconeogenesis, i.e. formation of glycogen from the amino acids and lipids.
• By decreasing intestinal absorption of glucose

Clinical trials show that metformin in diabetics reduces the fasting glycemia, glycosylated hemoglobin, blood cholesterol and triglycerides.
Metformin is not metabolized by biotransformations. It is present in the plasma in a free form, unbound toproteins. Its plasma half-life is about two to four hours. It is eliminated by the kidney and, in the event of renal impairment, risks to accumulating. The renal impairment is thus a contraindication to its prescription.
It is indicated in the treatment of type 2 diabetes mellitus not balanced by an adapted life style, particularly in overweight subjects. It is sometimes used as additive to insulin therapy in the treatment of insulin-dependant diabetes. Metformin could delay the mortality of the diabetics, especially the obese.
The most severe adverse effect of metformin is lactic acidosis, which can be fatal. Its premonitory signs are cramps, digestive disorders, intense abdominal pains, asthenia. These signs must lead to discontinuation of treatment and hospitalization. This lactic acidosis is seen especially in patients with renal or hepatic impairment. The diagnosis is confirmed by determination of blood lactic acid.
It can have other adverse effects: various digestive disorders, nausea, vomiting, diarrhea, especially at the beginning of treatment.
Metformin must be stopped before a radiological examination using iodized contrast agents because they are hyperosmolar and create a cellular dehydration, likely to induce lactic acidosis.

Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
 

On 9/17/09, ImmunoCellular Therapeutics (follow previous link for IMUC’s Facebook page) (IMUC.OB) ($1.11, +3%) (heavy, above-average volume) announced that the Company is featured in an in-depth industry research report published by Griffin Securities earlier this week which focuses on the importance of targeting cancer stem cells (CSCs) as a new, add-on approach to the treatment of cancer. The report highlights the stem cell hypothesis of cancer, which postulates that all tumor types have a common cell group of CSCs that typically account for a very small proportion of all cancer cells, but which are resistant to standard treatments and responsible for the spread and recurrence of the disease.
IMUC’s ICT-121 is an example of active cancer immunotherapy that is being developed as an off-the-shelf antigen to stimulate the immune system to recognize a nine amino acid epitope of CD133, which is found on many different types of CSC. IMUC has a patent on this molecule and on its use as a vaccine and expects to begin a Phase I/II clinical trial in early 2010. In addition, IMUC is developing a passive immunization approach to combating cancer through a monoclonal antibody discovery platform and recently signed a deal worth up to $32 million with Roche (RHHBY.PK) for ICT-69 in the diagnosis and treatment of multiple myeloma and ovarian cancer.
Two new categories have been added to the BioMedReports.com research section for industry reports and medical/scientific publications, including a new report uploaded earlier this week that was written by Keith Markey, PhD, of Griffin Securities on the emerging field of cancer stem cells (CSCs). The report highlights a variety of companies and therapeutic approaches aimed at targeting the emerging stem cell theory of cancer. In addition, four new scientific publications and articles were uploaded for privately-held Quantum Immunologics (QI) related to its experimental dendritic cell (DC) cancer immunotherapy (CI) that targets OFA-iLRP (oncofetal antigen – immature laminin receptor protein) as a universal cancer antigen.