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Old 06-17-2009, 06:47 PM   #21
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PI3 k akt pathway inhibitin thought to work against CSCs:



1: Thromb Res. 2008;122(2):191-202. Epub 2007 Nov 26. Links
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.

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]


More on simvistatin:

1: Cancer Lett. 2007 Jun 8;250(2):220-8. Epub 2006 Nov 27. Links
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
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Old 06-21-2009, 01:04 PM   #22
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1: Stem Cells. 2009 Apr 23. [Epub ahead of print] Links
Antigen-Specific T Cell Response from Dendritic Cell Vaccination Using Cancer Stem-like Cell-Associated Antigens.

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.
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Old 06-21-2009, 08:15 PM   #23
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June 18, 2009 08:00 AM Eastern Daylight Time
ImmunoCellular Therapeutics Announces Filing of Key Patent Application Relating to Cancer Stem Cell Technology


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
ImmunoCellular Therapeutics (IMUC.OB) is an emerging cancer immunotherapy company that is developing therapeutic and diagnostic product candidates taking aim at the root cause of the disease, cancer stem cells (CSCs), based on two distinct technology platforms - active (cancer vaccines) and passive (monoclonal antibodies or mAbs). This approach is in the early stages of development, but has the potential to become a disruptive, paradigm shifting therapeutic approach to the treatment of cancer. CSCs are resistant to standard treatments such as chemotherapy and radiation, but numerous bio-markers on these cells have been identified which can be used to develop targeted mAbs and CSC immunotherapy products.
Although CSCs account for a small proportion of the cells in a given tumor, a growing body of scientific literature suggests CSCs drive the process of tumor growth and recurrence (even after the disease is undetectable and thought to be eradicated). Current therapeutic options such as radiation therapy or chemo target the proliferating cells, which form the bulk of any tumor mass while the CSCs lie dormant and unaffected at the root of the disease. Click here for a link to several overview articles on CSCs at MIT's Technology Review website.
The Company is developing an off-the-shelf (i.e. does not require obtaining cells from the patient as part of the manufacturing process) stem cell cancer vaccine (ICT-121) which targets a protein marker called CD133 which is typically expressed only on cancer stem cells and not on normal cells. CSCs are responsible for the prolific growth of primary and metastatic tumors and these cells must be eliminated for the complete eradication of a tumor to prevent recurrence of the disease (which may occur after months or years of being free of cancer).
While glioblastoma (GBM, a deadly type of brain cancer) will be the initial target for ICT-121, CD133 is also over-expressed in a wide variety of cancers such as colon cancer, breast cancer, liver cancer, prostate cancer, multiple myeloma and melanoma. In late June, IMUC announced an agreement with Formatech, Inc. to manufacture the Company's CSC vaccine product candidate (ICT-121) for an upcoming Phase 1 clinical trial in early 2010 targeting GBM. The deal includes a provision for Formatech to prepare the cancer vaccine vials for the clinical trial in a FDA-compliant GMP (Good Manufacturing Practices) environment.
The Phase 1 study for ICT-121 will involve 20 patients with GBM receiving five treatments each with final data from the trial anticipated after about 18 months (e.g. 3Q11), since the median time to recurrence in GBM patients is only 6.9 months. The Company is focusing on the following deadly forms of cancer which represent unmet medical needs with the following incidence of new cases each year according to American Cancer Society statistics for 2008: brain (21,800), small-cell lung (215,020), and pancreatic cancer (37,680). These cancers represent an unmet medical need with a 15% five-year survival rate for this trio, compared to a five-year survival rate for breast cancer that is nearly 6X higher. A major problem is the recurrence of disease after initial treatment which is IMUC's target by focusing on residual disease (CSCs) following surgery in combination with standard radiation/chemo treatments.
IMUC uses peptides (the building blocks of proteins comprised of amino acid chains) in combination with another compound called an adjuvant to elicit a targeted immune response by T cells to destroy CSCs. This T cell response targets CSCs with a specific bio-marker (CD133 positive CSCs) that has been identified in a number of cancer types such as those outlined earlier. The goal of the Company's cancer vaccine approach is to combine conventional treatment(s) such as chemo or radiation with a product such as ICT-121 to target the residual CSCs to eliminate or delay the recurrence of cancer following treatment.
The current treatment for brain cancer (GBM) typically involves a combination of surgery, radiation treatment, and chemotherapy which may lead to tumor cell DNA mutations or other changes leading to treatment-resistance and/or tumor recurrence. At ASCO 2009, IMUC presented promising Phase 1 clinical data for ICT-107, which is the Company's dendritic cell-based cancer vaccine product candidate for the treatment of GBM (the most common and malignant type of brain cancer). The data presented at ASCO supplement the preliminary data from the completed study that IMUC initially reported in December 2008. The study enrolled 19 patients, including 16 with newly-diagnosed and three with recurrent disease. IMUC will seek a partnership to fund the future clinical development of ICT-107 as it focuses its resources on ICT-121 and cancer mAbs.
ICT-107 is the Company's patient-specific therapeutic cancer vaccine (in contrast to ICT-121 as an off-the-shelf vaccine) product candidate that consists of dendritic cells (immune system cells also referred to as antigen presenting cells or APCs that present molecules to the immune system to elicit a reaction) which are obtained from the patient's blood and programmed with tumor antigens which in turn provide a target for the immune system. Patients in the Phase I trial received three intradermal injections of ICT-107 at two-week intervals.
Seven of the 16 newly-diagnosed patients demonstrated stable disease with median progression-free survival of 64 weeks, and three of these seven patients have progression-free survival (PFS) exceeding two years, compared to the historical median PFS time of newly-diagnosed glioblastoma of just 30 weeks. ICT-107 was well tolerated with no significant adverse events (with no grade 3/4 adverse events and only mild side effects) reported in the study. Nine of the 16 newly-diagnosed patients had progressive disease with a median PFS of 39 weeks and median survival of 56 weeks. The three patients enrolled with recurrent disease exhibited disease progression, but still exhibited extended survival times of 34, 47, and 59 weeks.

Surasak Phuphanich, M.D., the principal investigator of the trial and a senior author of the ASCO presentation, stated that, "With a historical median PFS time of 6.9 months in GBM, we are encouraged to see a median PFS time of 14.2 months (57.5 weeks) in this newly-diagnosed glioblastoma (16 patients) population, and furthermore, it is exciting to see the correlation between immune response and survival given that the goal of ICT-107 is to elicit a cancer-specific immune response." A total of 15 patients in the trial were evaluated for immune responses, and six of them had a significant immune response to at least one tumor-associated antigen.
In early 2008, IMUC acquired a technology platform from Molecular Discoveries, LLC which referred to as DIAAD (Differential Immunization for Antigen and Antibody Discovery) for the rapid discovery of antigen targets to develop mAbs for the diagnosis and treatment of a wide variety of conditions with a focus on the detection and treatment of multiple myeloma, small cell lung cancer, pancreatic cancer, and ovarian cancer. The mAbs that IMUC acquired from Molecular Discoveries have been created to recognize certain bio-markers (antigens) which are highly specific to cancer cells and not expressed on normal cells to allow for the targeted treatment and detection of cancer cells.
The Company's mAb pipeline includes the following: (1) ICT-109 is a humanized mAb in development for the diagnosis of SCLC and pancreatic cancers; (2) ICT-037 is in preclinical development for therapeutic and diagnostic applications for colon cancer, ovarian cancer, and multiple myeloma; and (3) ICT-69 is in preclinical development for multiple myeloma and ovarian cancer.
The BioMedReports.com stock research section has recently been updated to include a research report for IMUC published by Griffin Securities on 4/27/09 with a buy rating and $2.50 price target (12-month) in addition to the most recent corporate presentation for the Company.
The report presents both a discounted cash flow and transactions analysis models, which value IMUC shares at $2.50 and $3.10, respectively. On 8/18/09, IMUC's President and CEO, Manish Singh, Ph.D., presented an overview of the Company's business and strategy at the Southern California Investor Conference which I have uploaded in PDF format to provide a single file with all of the slides and images along with a link to the audio transcript from the event. Click here to visit IMUC's page on Facebook.
IMUC is also one of 10 components in the Mentor Capital Cancer Immunotherapy (CI) Index, which has posted a gain of about 23% since its inception six weeks ago. The equal-weight CI Index tracks the following stocks: Mentor Capital (MNTR.PK) (as a public-traded proxy for tracking Quantum Immunologics), Dendreon (NASDAQNDN), ImmunoCellular Therapeutics, Antigenics (NASDAQ:AGEN), Biovest (BVTI.PK), Celldex Therapeutics (NASDAQ:CLDX), Oncothyreon (NASDAQ:ONTY), Northwest Biotherapeutics (NWBO.OB), CEL-SCI Corp. (AMEX:CVM), and Generex Biotechnology (NASDAQ:GNBT) ( as a proxy for its wholly-owned immunotherapeutic subsidiary, Antigen Express).
The CI Index is primarily a subset of my actively managed Cancer Diagnostic & Therapeutic (Dx/Tx) Micro-Cap Index, which reflects a cross-section of emerging cancer companies with market caps below $250 million at the time of index inclusion. In addition, Mentor Capital expects to update the CI Index on a weekly basis at its website.
As of the Company's most recent SEC 10Q filing on 8/14/09, IMUC had 14.65 million (M) shares of common stock outstanding, 9.7M options outstanding (at weighted average exercise price of $1/share or about 2X the current stock price of $0.55 as of 8/25/09), a market cap of $8M, zero debt, $2.3M in cash + investments, and a current cash burn rate of just $0.5M per quarter. In addition, IMUC has a strong intellectual property (IP) position, including seven issued patents and 17 pending applications that cover composition of matter, therapeutic treatments, and diagnostics related to CSC mAbs. Early next year (1Q10), IMUC expects to make an IND filing with the FDA for permission to begin human clinical trials for a Phase 1 study of its off-the-shelf cancer stem cell vaccine candidate (ICT-121).
The Company plans to raise $4-5M (sufficient to fund operations for 2.5 years) through a PIPE transaction with warrant coverage to fund Phase 1 trials of ICT-121 in GBM, pancreatic, and lung cancer; in addition to developing mAbs and additional vaccine candidates targeting CSCs. Any pending catalysts in the form of preclinical/clinical data, IND clearance to begin the Phase 1 trial for ICT-121, and development partnerships will have a major impact on IMUC given its low share count (less than 15M shares outstanding) and conservative valuation (market cap of about $8M) which ignores the Company's strong IP position as a pioneer in the emerging field of both active (vaccines) and passive (mAbs) immunotherapy product candidates focused on the root cause of cancer and its recurrence (CSCs).
Because of the very low cash burn rate of about $0.5M/quarter and $2.3M in cash + investments (sufficient to fund operations through at least mid-2010), IMUC has the luxury of waiting for higher stock prices before raising additional capital as the market becomes aware of the Company's prospects following expected catalysts before year-end that include partnership(s) for its CSC-targeting mAbs and feasibility data for ICT-109 in the detection of SCLC. Beyond 2009, value-enhancing catalysts include preliminary clinical data for ICT-121 (e.g. immune response data), a potential partnership to fund further clinical development of ICT-107, the generation of additional CSC mAbs and vaccine product candidates, and additional partnerships for mAbs beyond the deal expected to occur before year-end.




IMUC’s ICT-107 vaccine product candidate targets cancer stem cells

21. January 2010 04:40


ImmunoCellular Therapeutics (OTC.BB: IMUC) today announced the results of a study in which it was shown that certain specific antigens are highly expressed on cancer stem cells (CSCs). This suggests that IMUC’s lead cancer vaccine product candidate ICT-107, which targets those antigens, may effectively target not only the cells that make up the bulk of certain cancerous tumors, but also the CSCs that are widely believed to give rise to them and cause their recurrence.
“We believe that the ability to target cancer stem cells is critical to preventing disease recurrence.”
The CSCs used in IMUC’s study were isolated from the tumors of five patients with glioblastoma multiforme (GBM), the most common and aggressive type of brain cancer. These CSCs were found to have significantly higher expressions of three antigens targeted by ICT-107—Her-2/neu, AIM2, and TRP-2—than the cells that make up the bulk of the tumor.
“This new evidence that ICT-107 may arm the immune system against cancer stem cells— in addition to the cells that make up the rest of the tumor—builds on the strong data from our Phase I study of the vaccine in glioblastoma,” said John Yu, MD, IMUC’s Chairman and Chief Scientific Officer. “We believe that the ability to target cancer stem cells is critical to preventing disease recurrence.”
Manish Singh, PhD, President and CEO of IMUC, added, “Cancer stem cells are like the roots of weeds—they may be undetectable after the tumor is resected, but if they are not effectively targeted, the tumor will almost certainly come back. We believe the ability of ICT-107 to target cancer stem cells meaningfully differentiates it from other cancer vaccines in development.”
In a recent Phase I study of ICT-107 in GBM, newly diagnosed patients who received the vaccine demonstrated a 12-month increase in progression-free survival (PFS) after surgery. This compared favorably with the historical median PFS of 6.9 months observed with standard treatment with surgery, radiation and chemotherapy. Seven of the 16 patients who participated in the study continue to survive with no disease progression after more than two years.
ICT-107 is a dendritic-cell based vaccine that works by activating a patient’s immune system against specific tumor-associated antigens. This is accomplished by extracting dendritic cells from a patient, loading them with the antigens, and reintroducing them to the patient’s body to trigger an immune response.
The six tumor-associated antigens used in ICT-107 are AIM2, Her-2/neu, gp-100, MAGE-1, TRP-2 and IL13Ra2. These antigens are highly expressed in GBM as well as a number other types of cancer, including breast, pancreatic, colon and melanoma. ICT-107 may, therefore, be applicable to multiple cancer types.
SOURCE ImmunoCellular Therapeutics, Ltd.


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Old 06-21-2009, 08:45 PM   #24
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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.




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




Distinguishing Friend from Foe in the Battle Against Cancer

http://www.physorg.com/news77201870.html

excerpt:

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.”


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Old 06-28-2009, 07:22 PM   #25
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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.

1: Cancer Sci. 2009 Sep 1. [Epub ahead of print] Links
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
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Old 07-06-2009, 06:33 PM   #26
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Researcher’s Discovery Points to a New Treatment Avenue for Acute Myeloid Leukemia

published in Cell Stem Cell July 2, 2009
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LEUKEMIA, CANCER, STEM CELLS
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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.




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.
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Old 07-09-2009, 12:21 PM   #27
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Dendritic cell vaccines for cancer stem cells.

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
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Old 07-14-2009, 05:16 PM   #28
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1: J Immunol. 2009 Jun 1;182(11):7287-96. Links

Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes.

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.
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.
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Old 07-18-2009, 10:38 AM   #29
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Links CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells.

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

AM Rogan, TC Hamilton, RC Young, RW Klecker Jr, and RF Ozols

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.
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Old 07-26-2009, 10:26 PM   #30
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1: Cancer Res. 2008 Jul 15;68(14):5706-15. Links
Temozolomide preferentially depletes cancer stem cells in glioblastoma.

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.
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Old 07-29-2009, 04:28 PM   #31
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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
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.”
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Old 07-30-2009, 09:29 PM   #32
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Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce

Stemline Therapeutics CEO to Present at IBC's New Frontiers in Cancer Drug Development Conference

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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Old 08-14-2009, 02:30 PM   #33
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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
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Old 08-15-2009, 04:01 PM   #34
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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.

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, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin.
Conclusion Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.
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 Oncology Congress, Vienna, Austria, October 29–November 2, 2004, and the 27th San Antonio Breast Cancer Conference, San Antonio, TX, December 8-11, 2004.
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Old 08-27-2009, 08:45 PM   #35
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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 (23 November 2009) | doi:10.1038/onc.2009.392
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.

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
Plant Compound Blocks Action of Cancer Genes
http://www.hhmi.org/news/beachy.html

Quote:
"It had long been known that animals that consumed plants containing cyclopamine suffered severe neural birth defects, including malformations that produced a single cyclopic eye," said Beachy. "And when we knocked out the mouse counterpart of the hedgehog gene, Sonic hedgehog, we saw an effect very much like that produced in animals by cyclopamine. So, that really rang a bell for us."
After initial experiments indicated that cyclopamine did not directly affect the Hedgehog protein, the scientists turned their attention to the two cellular targets that receive signals from Hedgehog-proteins produced by the genes Smoothened and Patched. While the Smoothened protein switches on cell division, the Patched protein acts as a cellular "brake," or tumor suppressor. Previous studies had shown that Hedgehog switches on cell division by binding to Patched, turning off its normal braking function, and allowing Smoothened to activate cell proliferation.
The scientists' experiments ruled out that cyclopamine might thwart proliferation by activating the Patched protein. They found instead that when they deleted the Patched gene from mouse cells, cyclopamine could still turn off cell division. "Thus, we'd eliminated two red herrings-that cyclopamine affected either Hedgehog or Patched," said Beachy.
http://www.hhmi.org/research/investigators/beachy.html
Hedgehog Signaling in Development and Disease

Quote:
Our studies show that treatment with the Hedgehog pathway antagonist cyclopamine can block cell proliferative effects associated with pathway activation and can cause complete regression of aggressive human and rodent cancers growing in mice. The use of cyclopamine or other pathway antagonists thus may represent a novel, nontoxic approach to therapies for lethal human cancers.
1: J Med Chem. 2009 Jul 23;52(14):4400-18. Links


Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).

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.


PMID: 19522463 [PubMed - indexed for MEDLINE




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]


High content of zerumbone in volatile oils of Zingiber zerumbet from southern India and Malaysia

http://www3.interscience.wiley.com/j...17925/abstract

Sabulal Baby 1 *, Mathew Dan 2, Abdul R. M. Thaha 2, Anil J. Johnson 1, Rajani Kurup 1, Prasanth Balakrishnapillai 1, Chong Keat Lim 3
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
email: Sabulal Baby (sabulal@gmail.com)
*Correspondence to Sabulal Baby, Phytochemistry and Phytopharmacology Division, Tropical Botanic Garden and Research Institute, Pacha-Palode, Thiruvananthapuram 695 562, Kerala, India

Abstract
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.

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]
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Old 08-28-2009, 08:13 AM   #36
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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]


ABCG2: the key to chemoresistance in cancer stem cells?

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.

http://www.medicalnewstoday.com/articles/165763.php
10/1/09 Less toxic alternative to Imatinib
Masitinib - Targeted Therapy For Cancers, Inflammatory Diseases And Neurological Indications
In new research published in the open-access, peer-reviewed scientific journal PLoS ONE, Dr Patrice Dubreuil and colleagues characterise the pharmacological profile of masitinib (AB1010), a novel tyrosine kinase inhibitor (TKI) that targets the stem cell factor (KIT), PDGFR and Lyn. Masitinib is the active pharmacological ingredient of the first ever registered veterinary anticancer drug, Masivet® (1). The main cellular targets of masitinib are mast cells, meaning this drug also has many potential non-oncology applications. Indeed, Masivet® is in phase II/III trials for canine atopic dermatitis, inflammatory bowel disease and arthritis; as well as feline asthma. Additionally, promising results have been reported from human clinical trials of masitinib in rheumatoid arthritis (2), asthma (3) and mastocytosis.

Patrice Dubreuil from INSERM worked with scientists from several French research institutes and hospitals to carry out this work. He said, "This study shows that masitinib targets cell receptors known to be involved in various disease processes but due to its selectivity profile, it does not affect those associated with toxicity. In vitro, masitinib had greater activity and selectivity against KIT than the benchmark TKI, imatinib. Masitinib also more strongly inhibited mast cell degranulation, cytokine production, and migration than imatinib. In vivo, we show that masitinib can block tumour growth in mice".
Alain Moussy from AB Science, a pharmaceutical company which is developing masitinib for multiple indications in human and animal medicine, commented, "This is an important paper for us, being the cornerstone publication of masitinib's inhibitory profile". Speaking about the drug's future development, he said, "Masitinib is in numerous phase II/III clinical trials for both human and veterinary medicine. We anticipate that masitinib will be effective for the treatment of KIT and PDGFR-dependent diseases, which include various cancers, inflammatory diseases, and neurological indications, and that it will have a better safety profile, especially regarding cardiotoxicity and carcinogenicity, than other KIT inhibitors."
Citation:
"Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT."
Dubreuil P, Letard S, Ciufolini M, Gros L, Humbert M, et al. (2009)
PLoS ONE 4(9): e7258. doi:10.1371/journal.pone.0007258

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]

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Old 09-09-2009, 08:13 PM   #37
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Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce

1: J Control Release. 2008 Jul 2;129(1):18-25. Epub 2008 Apr 4. Links

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.

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]



1: Breast Cancer Res Treat. 2008 Oct;111(3):419-27. Epub 2007 Oct 27. Links

NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells.

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

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 Nakshatri1,2,3,4, Susan E Rice5 and Poornima Bhat-Nakshatri3,4
  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-B 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-B 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-B, 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-B, 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. Links

Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach.

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
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Old 09-11-2009, 12:38 AM   #38
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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]
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Old 09-14-2009, 10:16 PM   #39
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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.

1: Cancer Res. 2009 Sep 14. [Epub ahead of print] Links
Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission.

link to FULL TEXT

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].

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.
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Old 09-18-2009, 12:49 PM   #40
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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.
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