Peer-reviewed Articles Further Define Clusterin and the Role of a Clusterin Inhibitor, OGX-011, for the Treatment of Cancer
Researchers provide the first evidence that clusterin acts as a ubiquitin-binding protein, tagging COMMD1 and I-kB for degradation, and thereby activating the NF-kB pathway. COMMD1 and I-kB are enzymes known to regulate NF-kB, an important transcription factor responsible for regulation of immune response. Incorrect regulation of NF-kB is responsible for the production of several genes associated with cell survival, cell proliferation and anti-cancer treatment resistance. Importantly, researchers found that knockdown of clusterin in prostate cancer cells stabilizes COMMD1 and IkB thereby decreasing NF-kB activity, and consequently decreasing the production of genes associated with tumor cell survival and cancer treatment resistance.
Abstracts are available at the following AACR publication Web sites:
"Targeting the Cytoprotective Chaperon, Clusterin, for Treatment of advanced Cancer"
Amina Zoubeidi, Kim Chi, Martin Gleave
Clinical Cancer Research, February 15, 2010; 16(4); 1088-93;
"Clusterin Facilitates COMMDI and I-kB Degradation to Enhance NF-kB Activity in Prostate Cancer Cells"
Amina Zoubeidi, Susan Ettinger, Eliana Beraldi, Boris Hadaschik, Anousheh Zardan, Leo W.J. Klomp, Colleen C. Nelson, Paul S. Rennie, and Martin E. Gleave
Molecular Cancer Research, January 2010; 8(1);119-130;
"The links between clusterin (CLU) and NF-kB began when a two-hybrid approach identified COMMD1 as a CLU binding protein and gene profiling identified NF-kB-regulated genes coordinately altered by CLU, defining a novel mechanism whereby stress-induced increases in CLU activates the NF-kB signalosome," said Amina Zoubeidi, Assistant Professor at University of British Columbia and Vancouver Prostate Centre and lead author on the studies. "It is noteworthy that both CLU and NF-kB are activated in cancer cells by chemo- and radiation therapy and are associated with acquired anti-cancer treatment resistance, including castrate resistant prostate cancer."
"Mechanisms by which CLU exerts its pro-survival effects are becoming better elucidated, as featured in the February 15 issue of Clinical Cancer Research," said Dr. Martin Gleave, a UBC Professor and Director of the Vancouver Prostate Centre. "CLU functions like small heat shock proteins to chaperone and stabilize conformations of proteins at times of cell stress, thereby inhibiting stress-induced protein aggregation." Dr. Gleave is also Chief Scientific Officer at OncoGenex.
About OncoGenex Pharmaceuticals
OncoGenex is a biopharmaceutical company committed to the development and commercialization of new cancer therapies that address treatment resistance in cancer patients. OncoGenex has a deep oncology pipeline, with each product candidate having a distinct mechanism of action and representing a unique opportunity for cancer drug development. OncoGenex and Teva Pharmaceutical have entered a global collaboration and license agreement to develop and commercialize OncoGenex's lead drug candidate, OGX-011. The companies expect to initiate two Phase 3 trials in castrate resistant prostate cancer in 2010, and a third Phase 3 trial in non-small cell lung cancer in early 2011; OGX-427 is in Phase 1 clinical development; SN2310 has completed a Phase 1 clinical trial; and CSP-9222 and OGX-225 are currently in pre-clinical development.
OGX-011, OGX-427 and OGX-225 utilize second-generation antisense technology, licensed from Isis Pharmaceuticals (NASDAQ: ISIS), to target and inhibit production of specific proteins which OncoGenex believes are important in tumor progression and treatment resistance. OncoGenex and Isis partnered in the successful discovery of OGX-011, OGX-427 and OGX-225 and with respect to OGX-011, in its initial development. In 2008, OncoGenex and Isis amended their OGX-011 agreement to provide OncoGenex with sole rights to OGX-011 and sole responsibility for development and related costs and partnering decisions, subject to financial obligations to Isis. OncoGenex is also solely responsible for development and related costs and partnering decisions regarding OGX-427 and OGX-225. Key intellectual property related to OGX-011, OGX-427 and OGX-225 were discovered by the University of British Columbia and the Vancouver Prostate Centre, and were exclusively licensed to OncoGenex.
More information about OncoGenex is available at www.oncogenex.com.
OncoGenex' Forward Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements concerning anticipated clinical and other product development activities and timing and costs of these activities. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Such forward-looking statements are subject to risks and uncertainties, including, among others, the risk factors set forth in the Company's filings with the Securities and Exchange Commission, including the Company's Annual Report on Form 10-K for fiscal year 2008. The Company undertakes no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof, other than as may be required by applicable law.
SOURCE OncoGenex Pharmaceuticals, Inc.
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