Kosan's AACR Data Indicates Strong Synergy of Hsp90 Inhibitor, 17-AAG, in Preclinical Combination Chemotherapy Studies
Monday March 29, 8:06 am ET
ORLANDO, Fla., March 29 /PRNewswire-FirstCall/ -- Kosan Biosciences (Nasdaq: KOSN - News) announced today at the 95th Annual Meeting of the American Association for Cancer Research in Orlando, FL, preclinical in vitro data on the cytotoxic and antiproliferative effects of Kosan's lead Hsp90 inhibitor, 17-AAG, when used in combination with 20 different standard and novel chemotherapeutics. Data from the study demonstrated broad synergistic activity consistent with the mechanism of action of Hsp90 inhibition. Clinical investigation of several of these combinations in humans is ongoing.
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The poster presentation entitled "17-AAG (KOS-953), An Inhibitor of Hsp90 Function, Significantly Enhances the Cytotoxicity of Anticancer Drugs: An Effective Approach for Combination Therapy" (Abstract #1992) presented data demonstrating that 17-AAG, an analog of the polyketide geldanamycin, had synergistic effects with a broad range of anticancer agents in different tumor cell lines, suggesting that combining these agents with 17-AAG may enhance the effect of drug therapies by sensitizing tumor cells or potentiating their anticancer activity.
In the study, the antiproliferative effects of combining 17-AAG and over 20 different anticancer agents in the human colon cancer cell line DLD-1 and breast cancer cell line SKBr3 were evaluated. The anticancer agents represented a broad range of mechanisms including alkylating agents, antimetabolites, anticancer antibiotics, microtubule-interacting agents, and protein kinase inhibitors. The results showed that, in DLD-1 cells, approximately 80% of the drugs demonstrated synergistic effects with 17-AAG, whereas in SKBr3 cells, approximately 50% of the drugs showed synergistic effects. More than 25% of the drugs including microtubule-interacting agents docetaxel, vinblastine, vincristine and KOS-862 were synergistic with 17-AAG in the colon and breast cancer cell lines regardless of treatment schedule.
According to Daniel V. Santi, M.D., Ph.D., Chairman and Chief Executive Officer at Kosan Biosciences, "The preclinical data suggests that by inhibiting multiple signal transduction pathways at one time, we can boost the efficacy of other chemotherapeutic regimens. Because cancer cells can circumvent a single pathway inhibitor, the data suggests that our geldanamycin analogs may represent a powerful new chemotherapeutic approach by sensitizing cancer cells to certain other anticancer agents. Ongoing Phase Ib trials are evaluating the hypothesis in human clinical trials."
Clinical Development Background
In August 2003 Kosan Biosciences announced the initiation of several Phase Ib human clinical trials of 17-AAG in combination with other anticancer agents as part of a collaboration with the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) under Cooperative Research and Development Agreements (CRADAs) signed in 2002. The ongoing Phase Ib trials include 17-AAG in combination with gemcitabine and cisplatin in patients with solid tumors, with imatinib mesylate (Gleevec®) in patients with chronic myeloid leukemia (CML), and with docetaxel (Taxotere®) in patients with advanced solid tumors.
The objectives of the Phase Ib studies are to test the safety of the combination, and to determine an appropriate dose and schedule for the use of 17-AAG in combination with these approved anticancer agents. Clinical investigators will monitor client proteins as pharmacodynamic biomarkers during treatment to verify the anticipated effects on the Hsp90 client proteins and to insure adequate drug exposure.
17-AAG inhibits Hsp90 (heat shock protein 90), a protein chaperone that binds to several sets of signaling proteins, known as "client proteins." These client proteins include a "who's who" list of cancer-relevant targets such as mutated p53, Bcr-Abl, Raf-1, ErbB2 and others. When 17-AAG binds to Hsp90 it causes disruption of the Hsp90-client protein complexes, which in turn leads to the degradation of the client proteins by the proteosome.
About Kosan
Kosan Biosciences has two lead product candidates: KOS-862 and 17-AAG. Both compounds are derived from an important class of natural products known as polyketides. KOS-862 is in Phase II clinical trials and is partnered with Roche in a global development and commercialization agreement. 17-AAG is being evaluated in multiple Phase I and Phase Ib clinical trials in collaboration with the National Cancer Institute. 17-AAG is a polyketide inhibitor of Hsp90 and interrupts several biological processes implicated in cancer cell growth and survival. By applying its expertise and proprietary technologies to generate polyketide analogs and by increasing the production yields of polyketides, Kosan has created a robust pipeline of potentially significant products for cancer, as well as for infectious disease and other therapeutic areas. For additional information on Kosan Biosciences, please visit the company's website at www.kosan.com. |
