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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (645)	1/25/2006 7:39:51 AM
From: nigel bates	Read Replies (1) \| Respond to of 933

Kosan Initiates Phase I Clinical Trial of Oral Hsp90 Inhibitor KOS-1022 Wednesday January 25, 7:30 am ET HAYWARD, Calif., Jan. 25 /PRNewswire-FirstCall/ -- Kosan Biosciences Incorporated (Nasdaq: KOSN - News) today announced that it has initiated a Phase I multicenter trial of an oral formulation of KOS-1022 (DMAG), a second-generation heat shock protein 90 (Hsp90) inhibitor. KOS-1022 is the first-reported Hsp90 inhibitor to be administered orally to patients with cancer. "Initiation of clinical testing of an oral formulation of KOS-1022 complements the development program for intravenous KOS-1022 and is an important step in our Hsp90 inhibitor program," said Daniel V. Santi, M.D., Ph.D., Kosan Chairman and Chief Executive Officer. "In addition, given the convenience of oral dosing compared to intravenous dosing, the capsule formulation of KOS-1022 will allow us to investigate whether more continuous inhibition of Hsp90 will lead to enhanced antitumor activity." The Phase I clinical trial of oral KOS-1022 will evaluate the safety, pharmacokinetics, pharmacodynamics, and bioavailability of escalating doses of KOS-1022 in patients with advanced solid tumors, as well as assess any preliminary evidence of antitumor activity. The clinical trial will be conducted at the University of Colorado Health Science Center and the Presbyterian Hospital Medical Center at the University of Pennsylvania. Intravenous KOS-1022 is currently being evaluated in a company-sponsored Phase I clinical trial in patients with hematologic malignancies as well as multiple Phase I clinical studies in patients with advanced solid tumors sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between Kosan and the NCI Cancer Therapy Evaluation Program. Because of the complementary nature of oral and intravenous KOS-1022, Kosan plans to continue to develop both formulations. In addition to oral and intravenous KOS-1022, Kosan's first-generation Hsp90 inhibitor, a proprietary formulation of 17-AAG (KOS-953), is being investigated by Kosan in a Phase II clinical trial in combination with trastuzumab (Herceptin®) in patients with Her2 positive breast cancer, as well as clinical trials in patients with relapsed refractory multiple myeloma (both as single-agent and in combination with bortezomib (Velcade®)). Kosan may initially seek approval for KOS-953, in combination with Velcade, to treat relapsed refractory multiple myeloma. In 2004, Kosan obtained orphan drug designation for 17-AAG from both the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of multiple myeloma as well as another hematologic cancer, chronic myelogenous leukemia. About Hsp90 Inhibitors KOS-1022 and 17-AAG are analogs of the polyketide geldanamycin that inhibit Hsp90. KOS-953 is Kosan's proprietary formulation of 17-AAG. Hsp90 is a molecular "chaperone" which maintains the stability of numerous "client proteins" implicated in tumor growth and metastasis, including protein kinases and transcription factors. By blocking the activity of Hsp90, geldanamycin analogs lead to disruption of the Hsp90-client protein complexes and client protein degradation. By targeting multiple growth-signaling pathways involved in cancer, these compounds may have potential use in a variety of tumor types, both as single agents and in combination with other signal transduction inhibitors and cytotoxic drugs. About Kosan Kosan Biosciences is advancing two new classes of anticancer agents through clinical development. Kosan is developing Hsp90 (heat shock protein 90) inhibitors in collaboration with the NCI. Kosan's proprietary formulation of 17-AAG (KOS-953) is in Phase I and II clinical trials for multiple myeloma and Her2 breast cancer. In addition, intravenous and oral formulations of a second-generation Hsp90 inhibitor, KOS-1022 (DMAG), are currently in Phase I clinical trials. Kosan is also developing KOS-862 (Epothilone D) in Phase II clinical trials in breast cancer, and a follow-on Epothilone D analog, KOS-1584, is in Phase I clinical trials. This program is partnered with Roche through a global development and commercialization agreement. Kosan has generated a pipeline of additional product candidates targeting gastrointestinal motility, infectious diseases and cancer based on its proprietary technologies for discovering, developing and manufacturing polyketide analogs. Polyketides are an important class of natural products that have yielded numerous pharmaceuticals for the treatment of cancer, infectious diseases, high cholesterol, transplant rejection and other diseases. For additional information on Kosan Biosciences, please visit the Company's website at www.kosan.com.

To: tuck who wrote (645)	2/8/2006 1:16:44 PM
From: tuck	Respond to of 933

[Sensitization of TRAIL–resistant cells by inhibition of HSP90 with low-dose geldanamycin ] >>Mol Cancer Ther. 2006;5:170-178 Sensitization of TRAIL–resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin Yulin Ma2, Vijayabaskar Lakshmikanthan2, Ronald W. Lewis2 and M. Vijay Kumar1,2 1 Department of Research, VA Medical Center and 2 Department of Surgery, Section of Urology, Medical College of Georgia, Augusta, Georgia Requests for reprints: M. Vijay Kumar, Department of Research, VA Medical Center, One Freedom Way, Augusta, GA 30904. Phone: 706-721-6620; Fax: 706-721-2548. E-mail: vkumar@mail.mcg.edu Due to its specificity and effectiveness, tumor necrosis factor-–related apoptosis-inducing ligand (TRAIL) is being tested for cancer therapy. Inhibition of the function of heat shock protein 90 (HSP90) is under clinical trials for cancer therapy. However, some cancer cells are resistant to TRAIL, and at the dose required for inducing apoptosis, geldanamycin, a drug that inhibits HSP90 function, has shown adverse effects. Therefore, our working plan was to identify a sublethal dose of geldanamycin and combine it with TRAIL to induce apoptosis in TRAIL-resistant prostate cancer cells. Treatment of LNCaP with 250 nmol/L geldanamycin inhibited HSP90 function but did not induce significant apoptosis. However, combination of geldanamycin and TRAIL induced highly significant apoptosis in TRAIL-resistant LNCaP cells. In addition to inducing caspase activity and apoptosis, treatment with geldanamycin and TRAIL decreased inhibitor of B (IB) kinase (IKK) complex proteins, IKK, IKKß, and IKK. The loss of IKK affected IB/nuclear factor-B (NF-B) interaction and reduced nuclear transport of NF-B, resulting in reduced NF-B activity. Our data show increase in apoptosis using low, suboptimal dose of geldanamycin when used with TRAIL. These results provide a means to alleviate two problems: resistance to TRAIL and adverse effects of high-dose geldanamycin.<< Cheers, Tuck