OncoGenex Pharmaceuticals, Inc. (NASDAQ: OGXI), announced today that two peer-reviewed articles have been published that further elucidate the biological function of clusterin, its role in promoting tumor resistance to cancer treatment, and the role of an inhibitor of clusterin such as custirsen (OGX-011) that is designed to knock down treatment resistance in the cells and enhance the effectiveness of cancer therapies. Researchers have defined another novel mechanism by which the knockdown of clusterin in cancer cells with OGX-011 may enhance treatment induced apoptosis.
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"