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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce
Cancer Immunol Immunother. 2009 Aug;58(8):1185-94. Epub 2008 Dec 2.
Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells.
Mine T, Matsueda S, Li Y, Tokumitsu H, Gao H, Danes C, Wong KK, Wang X, Ferrone S, Ioannides CG.
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. mine@med.kurume-u.ac.jp
Cancer stem cells (CSC) are resistant to chemo- and radiotherapy. To eliminate cells with phenotypic markers of CSC-like we characterized: (1) expression of CD44, CD24, CD133 and MIC-A/B (NKG2 receptors) in breast (MCF7) and ovarian (SK-OV-3) cells resistant to gemcitabine (GEM), paclitaxel (PTX) and 5-fluorouracil (5-FU) and (2) their elimination by Numb- and Notch-peptide activated CTL. The number of cells in all populations with the luminal CSC phenotype [epithelial specific antigen(+) (ESA) CD44(hi) CD24(lo), CD44(hi) CD133(+), and CD133(+) CD24(lo)] increased in drug-resistant MCF7 and SK-OV-3 cells. Similarly, the number of cells with expressed MIC-A/B increased 4 times in drug-resistant tumor cells compared with drug-sensitive cells. GEM(Res) MCF7 cells had lower levels of the Notch-1-extracellular domain (NECD) and Notch trans-membrane intracellular domain (TMIC) than GEM(Sens) MCF7. The levels of Numb, and Numb-L-[P]-Ser(265) were similar in GEM(Res) and GEM(Sens) MCF7 cells. Only the levels of Numb-L (long)-Ser(295) decreased slightly. This finding suggests that Notch-1 cleavage to TMIC is inhibited in GEM(Res) MCF7 cells. PBMC activated by natural immunogenic peptides Notch-1 (2112-2120) and Numb-1 (87-95) eliminated NICD(positive), CD24(hi) CD24(lo) MCF7 cells. It is likely that the immunogenic Numb-1 peptide in MCF7 cells originated from Numb, [P]-lated by an unknown kinase, because staurosporine but not wortmannin and MAPK-inhibitors decreased peptide presentation. Numb and Notch are antagonistic proteins which degrade each other to stop and activate cell proliferation, respectively. Their peptides are presented alternatively. Targeting both antagonistic proteins should be useful to prevent metastases in patients whose tumors are resistant to conventional treatments.
PMID: 19048252 [PubMed - indexed for MEDLINE]
New Drug Blocks "Undruggable" Target in Cancer Cells
Researchers have created a new type of cancer drug that blocks a “master” protein considered to be untouchable by conventional agents. A team from Harvard University used the drug to suppress signals from a growth-promoting pathway, the Notch signaling pathway, that switches on inappropriately in some cancers. Cancer cells that depend on Notch signaling die when the pathway is blocked, Drs. Gregory L. Verdine, James Bradner, and their colleagues reported in the November 12 Nature.
The drug’s primary target is Notch1, a transcription factor that regulates genes involved in the growth and survival of cells. Transcription factors are mutated in various cancers, but these proteins have proved difficult to target directly because of their structures.
To solve this problem, the Harvard team, led in the lab by graduate student Raymond Moellering, designed a drug molecule (called SAHM1) that enters cells and interferes with a protein-protein interaction that is essential for the transmission of cell growth signals via the Notch pathway.
The researchers tested the drug using cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of the disease. The Notch1 gene is mutated in half of patients with T-ALL and produces an inappropriately active Notch1 protein. Activated Notch signaling has been seen in several other cancers, including lung, ovarian, and pancreatic cancer, and melanoma.
“We’ve drugged a so-called undruggable target,” said Dr. Verdine. “This study validates the notion that you can target a transcription factor by choosing a new class of molecules, namely stapled peptides.” The strategy may work for other transcription factors because the molecular logic of these proteins is similar to that of Notch1, he added.
In an accompanying editorial, Drs. Paramjit Arora and Aseem Ansari said that the group’s “remarkable results highlight the potential of molecules that mimic the secondary structures of proteins to target normally intractable protein-protein interactions.”
SABC 2009
http://www.medpagetoday.com/MeetingCoverage/SABCS/17499
SABCS: Stem Cells a Promising Target in Breast CA
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SAN ANTONIO -- Targeting breast cancer stem cells with experimental "Notch" inhibitors appears promising in the fight against recurrence, researchers said here.
The novel agents, also known as gamma secretase inhibitors, reduced the number of cancer tumor cells, although with little immediate impact on tumor volume, Jenny Chang, MD, of Baylor College of Medicine in Houston, and colleagues found.
Their early phase experiments in mice and a small group of patients suggested a "paradigm shift" in looking at breast cancer treatment, Chang reported at the San Antonio Breast Cancer Symposium.
Conventional therapy largely aims at volume -- shrink and remove the tumor and keep the mass from regrowing, noted William Gradishar, MD, of the Lurie Cancer Center at Northwestern University in Chicago, who moderated a press conference at which the study was discussed.
But the roughly 1% of tumor cells dubbed "mother cells" that produce new stem cells and regular tumor "daughter" cells, typically survive chemotherapy, endocrine therapy, and radiation.Action Points
- Caution interested patients that the drugs used in the trial are still investigational and are not FDA approved for any use.
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
"The current available therapies really aren't affecting that population of cells," Gradishar added.
In fact, one prior study from Chang's group showed that the cancer stem cells actually more than tripled during neoadjuvant chemotherapy.
"The cancer stem cell hypothesis is that you need to kill both populations -- the bulk of the tumor as well as the cancer stem cells -- and they're regulated by different mechanisms," Chang said.
To find out what was driving these hardy cells, the researchers did a gene expression analysis, which revealed Notch signaling as the top candidate.
The Notch pathway is involved in normal mammary development, in communication between cells, and in determining what happens to a cell when it divides, thus "regulating the self-renewal of cancer stem cells," Chang said in an interview with MedPage Today.
She and her team implanted mice with human breast cancer biopsy material that included breast cancer stem cells, then gave them a Notch inhibitor (MRK-003) or a placebo.
MRK-003 significantly reduced formation of clusters of tumor cells called mammospheres compared with placebo.
Tumor volume dropped about fourfold over 21 days with the agent compared with about a threefold decrease with placebo or docetaxel alone or in combination with the Notch inhibitor, but the difference between groups was not significant, likely due to the short duration, Chang said.
With this evidence in hand, Chang's group started a Phase Ib/II clinical trial with another Notch inhibitor (MK-0752) -- 35 women were given the Notch inhibitor before each docetaxel administration for six cycles. Compared with baseline biopsies, those taken at the end of treatment had significantly fewer cancer stem cells measured by CD44/CD24 expression. The formation of mammosphere cell clusters fell significantly as well. Again, though, tumor regression wasn't seen immediately with Notch inhibition. It occurred only after several rounds of therapy. This likely reflects daughter cells dying off from chemotherapy with progressively fewer stem cells to repopulate them, Chang said. Given the proposed mechanism, Notch inhibitors are likely to be developed for upfront use in combination with agents to "debulk" the daughter cells or for chronic administration in the adjuvant setting to prevent recurrence, she speculated.
Her group plans a larger Phase II trial, while others are developing agents targeting other cancer stem cell pathways, such as Hedgehog.
"Trying to identify what really makes them grow, to interfere with those pathways may ultimately lead to better outcomes for patients with both early and advanced stage disease," Gradishar said.
The study was funded by Merck, which is developing the gama secretase inhibitor used.
Chang made no disclosures other than the funding for the study.
Gradishar reported being a consultant for Bayer and Nexavar.
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Primary source: San Antonio Breast Cancer Symposium
Source reference:
Chang J, et al "Targeting intrinsically-resistant breast cancer stem cells with gamma-secretase inhibitors " SABCS 2009; Abstract 48.
For the First Time, a Glioma - Brain Cancer - may be Eliminated by a Chinese Research/Medical Team, Using a Novel Stem Cell Based Therapy of Cellonis Biotech, Beijing
LINK
BEIJING, Dec. 17 2009/PRNewswire-Asia/ -- Using a novel stem cell based technology of Cellonis Biotechnologies, Beijing, a Chinese research/medical team may eliminate a glioma -- brain cancer -- of a 36 year old Norwegian patient in a hospital in Beijing. The treatment shows that the activated immune system can directly kill tumor stem cells as well as cancer daughter cells. The amazing outcome of this novel treatment within a Comprehensive Cancer Therapy tells Cellonis that the future vaccination therapies may be targeted towards cancer stem cell lysates to improve the antigen-presenting Dendritic Cell response.
(Photo: http://www.newscom.com/cgi-bin/prnh/20091217/CNTH007)
Arve Johnsen , 36, from Norway, a patient diagnosed with glioma in 2006 and relapsed in 2009 after surgical resection. He arrived in Beijing in August 2009 with his wife Vanja and a one-year-old daughter, with the hope that the doctors in Norway were wrong. They told the family there is no other option anymore in the Scandinavian countries or in Europe for Arve to control the progress of disease and prolong his life. Driven by the hope that their daughter could grow up with a father, the Johnsen family started a research campaign to find other treatments worldwide, to give Arve a new hope. Comprehensive Cancer Therapy in China
The Johnsen's, having heard about the sustainable success of a Comprehensive Cancer Therapy (CCT) in China, decided to try for this last chance in a country 10,000 km away from Norway. This kind of CCT had been developed in the past few years by a Chinese team of scientific researchers and clinical doctors in Beijing, combining conventional cancer treatments with Traditional Chinese Medicine (TCM) and cell therapies.
The role of cancer stem cells in the tumors cientists previously believed that tumors are lumps of cancer tissue that must be completely removed or destroyed to cure a patient. But over the past few years, researchers have learned that cancer stem cells (CSCs), comprising a small population of cells, appear to be responsible for the initiation, upkeep and relapse of malignant tumors. Even if a tumor is almost completely obliterated, it will regenerate from the surviving CSCs and become even more resistant to treatment than before.
Current therapies, including cell therapy, generally do not target CSCs. This allows CSCs to survive until after chemotherapy or radiation treatments. Killing those cells is a promising strategy to eliminate tumors and prevent them from re-growing.
Prof.
Lily Shum : Perfect integration of stem cells and immunotherapies
"The CSCs may explain why common treatments, particularly chemotherapy, are not sufficient to kill tumors. In fact, despite the continuous development of new chemotherapeutic agents, brain tumors can develop and remain resistant to those therapies. The integration of stem cells and immune technologies seems to give us a chance to find out a new way to target at CSCs," says Prof.
Lily Shum , PhD, the chief scientist of Cellonis. "The difficult issue in our project is how to capture and classify CSCs. With our patented technologies, we are able to isolate the CSCs from patient's brain tumor tissues, culture them and induce the multi-drug and radiation resistance. These cells possess very strong carcinogenicity, self-renewal, and also a very strong drug and radiation resistance."
Lily Shum adds, "The Dendritic Cell (DC) is a very useful tool to conduct a specific immune response against brain CSCs." As we know, DC is an antigen-presenting cell that stimulates the innate immune system, as a messenger, it transfers "the information of cancer cell - antigen" to "the killers of the immune system - the T cells," and then T cells can recognize and lyse cells bearing those antigens. "We educate the DC with the brain CSCs, and then conduct the specific immune response which targets the CSCs."
Dr.
Dinggang Li : Comprehensive Cancer Therapies
"The outcome of the first pilot study with Johnsen is amazing. The PET-CT scan for Johnsen shows that all the tumor disappeared after the treatment," says Dr.
Dinggang Li, M.D. PhD. He has developed and conducted CCT for more than 100 international cancer patients in the past few years. DCs loaded with different kinds of brain cancer related antigens that target cancer cells and the CIK cell treatment are the main elements of his comprehensive treatment for cancer. "In the first cycle of treatment, we treated him with comprehensive approaches including SHG-44 loading DC, CIK cell therapy and TCM, but we had not been able to control the progression of the disease, the tumors continued to grow. We gave him the DC therapy which targets brain CSCs in the 2nd cycle of treatment, and it showed a very promising response." Dr. Cindy HAO: More clinical trials to confirm the outcome
Cindy HAO, M.D., CEO of Cellonis Biotechnologies is optimistic for the future of this new brain cancer approach. "It gives us a strong confidence to make more efforts toward this direction. This pilot treatment study shows us that the activated immune system can directly kill tumor stem cells as well as tumor daughter cells. But first of all we need to extend our further clinical trials to confirm the outcome. And it also tells us that the future vaccination therapies may be targeted toward Cancer Stem Cell Lysates to improve the antigen-presenting DC response."
For more information, please contact:
Urs. J. Lienert, M.B.A.
Director International
Cellonis Biotechnologies Co., Ltd.
Floor 7, Huizhong Science & Technology Center
No 1, Shangdi Seventh Road
Haidian District Beijing, 100085
P.R. China
Email: urs.lienert@cellonis.com; Lienert.Cellonis@yahoo.com
Phone: +86-10-6296-2795; Cell: +86-150-1054-7487
Cell: +41-76-584-87-60 (Switzerland)
(from 20 December 2009 to 15 January 2010)
SOURCE Cellonis Biotechnologies
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