Peer-reviewed Research Elucidates Function of Hsp27; Supports OGX-427 Approach Targeting Cancer Treatment Resistance
BOTHELL, WA and VANCOUVER, BC – March 15, 2010 – (Canada NewsWire via COMTEX News Network) – OncoGenex Pharmaceuticals, Inc. (NASDAQ: OGXI), announced today that two peer-reviewed manuscripts have been published that provide additional insight into the function of Heat Shock Protein 27 (Hsp27) and its role in promoting tumor resistance to cancer treatment. The Company’s drug candidate OGX-427 is designed to reduce levels of Hsp27, a protein that is overproduced in response to many cancer treatments including hormone ablation therapy, chemotherapy and radiation therapy. Two recently published peer-reviewed manuscripts describe the signaling pathways by which Hsp27 mediates tumor cell survival, providing additional rationale for inhibiting Hsp27 as a therapeutic approach for cancer treatment.
In a manuscript published in Cancer Research, researchers define the links between Hsp27 phosphorylation and Insulin-like growth factor-1 (IGF-1) signaling in prostate cancer. IGF-1 is a well documented stimulator of cell growth and proliferation, and a potent inhibitor of programmed cell death. Researchers show for the first time that Hsp27 is directly phosphorylated by p90Rsk kinase as a result of IGF-I signaling. Phosphorylation of Hsp27 promotes cell survival by stabilizing Bad/14-3-3 protein complexes. Conversely, Hsp27 knockdown, such as with OGX-427 treatment, blocks IGF-1 induced phosphorylation of p90Rsk thereby destabilizing Bad/14-3-3 complexes and increasing programmed cell death.
“Hsp27 Promotes Insulin-Like Growth Factor-I Survival Signaling in
Prostate Cancer via p90Rsk-Dependent Phosphorylation and Inactivation
Zoubeidi, et al, Cancer Research, March 15, 2010; 70(6); 2307-17
In a separate manuscript published in Oncogene, researchers identify a mechanism by which changes in Hsp27 expression serve as an upstream regulator of eIF4E, a key regulator for protein synthesis. By chaperoning eIF4E, Hsp27 protects the protein synthesis initiation process to enhance cell survival during cell stress induced by castration or chemotherapy. Furthermore, Hsp27 knockdown using OGX-427 correlated with a significant decrease in the expression of eIF4E. Researchers conclude that OGX-427-mediated Hsp27 knockdown reduces eIF4E stability, enhancing its degradation, thereby reducing cancer cell viability after androgen withdrawal or chemotherapy.
“Heat shock protein 27 confers resistance to androgen ablation and
chemotherapy in prostate cancer cells through eIF4E”
Andrieu, et al, Oncogene advance online publication, January 18,
“Further insight into the mechanism of action of Hsp27 and the characterization of additional cell survival proteins will improve our understanding of the regulatory pathways in cells for preventing programmed cell death, leading to drug resistance in cancer treatment,” said Dr. Martin Gleave, a UBC Professor, Director of the Vancouver Prostate Centre and a co-author on the papers. Dr. Gleave is also Chief Scientific Officer at OncoGenex. “This research suggests that knockdown of Hsp27 by OGX427 treatment may counter the cell survival mechanisms involved in cancer treatment resistance, and supports further investigation of OGX-427 in clinical trials.”
OGX-427 is designed to reduce levels of Hsp27, a protein that is over-produced in response to many cancer treatments including hormone ablation therapy, chemotherapy and radiation therapy. Hsp27 production has been shown to inhibit cell death in tumor cells through a variety of mechanisms.
OncoGenex expects that a randomized, controlled, investigator-sponsored Phase 2 clinical trial evaluating OGX-427 when administered as a monotherapy to patients with CRPC will initiate in mid-2010.
In August 2009, OncoGenex announced the first patient dosed in an open label, dose-escalation, Phase 1 clinical trial evaluating OGX-427 when administered directly into the bladder in patients with bladder cancer. The study, which will enroll up to 36 patients with bladder cancer, is designed to determine the safety and potential benefit of OGX-427 administered directly into the bladder using a catheter, which is called intravesical instillation. In addition, the study will measure the direct effect of OGX-427 on expression of Hsp27 in bladder tumor cells as well as determine the pharmacokinetics and pharmacodynamics of OGX-427 when delivered by intravesical instillation. The study is sponsored by the National Cancer Institute of Canada (NCIC).
OGX-427 is also being evaluated in a separate Phase 1 clinical trial for the systemic (intravenous) treatment of solid tumors including prostate, non-small cell lung, breast, ovarian, and bladder cancers. OncoGenex announced preliminary results of this Phase 1 trial presented during an oral presentation at the 2009 American Society of Clinical Oncology (ASCO) Annual Meeting. Results as of May 2009 showed that OGX-427 was well tolerated as a monotherapy. In addition, after treatment with OGX-427 most patients experienced declines in circulating tumor cells at all doses evaluated as well as evidence of reduction in tumor markers. Reductions in circulating tumor cells and tumor markers suggest single-agent activity warranting further clinical investigation.
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 project to initiate two Phase 3 trials in castrate resistant prostate cancer in Q2 and Q3 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. 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 the role of Hsp27 in treatment resistance, the clinical potential of OGX-427, 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 2009. 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