WASHINGTON, DC USA (UroToday.com) - Stress activates heat shock chaperones after castration. Heat shock proteins protect the proteome against misfolding and aggregation, but in cancer their functions are subverted to facilitating oncogenesis. Clusterin (CLU) is a versatile chaperone molecule of which there is a cytoplasmic and secreted form. sCLU-2 is a treatment induced form identified in cancer models. It is activated by treatment stress such as castration and androgen withdrawal. CLU over-expression confers broad-spectrum treatment resistance to castration, radiation and chemotherapy. Clu levels increase after endoplasmic reticulum (ER) stress and can result in activation of autophagy. Autophagy is a lysosomal degradation pathway for intra-cellular digestion, but can confer stress tolerance and viability under adverse conditions. Autophagy is inhibited via mTOR signaling. ER stress-induced autophagy is inhibited by CLU silencing. CLU affects levels of autophagy substrate proteins, such as Huntington protein. Antisense Clusterin called OGX-011 can knockdown Clu and induce apoptosis. OGX-011 sensitizes prostate cancer cells to taxanes and radiotherapy. It also enhances castration-induced apoptosis in animal models. OGX-011 synergistically enhanced MDV3100 activity in castrate-resistant LNCaP tumors in mice. OGX-011 also enhances Hsp90 inhibitor activity in LNCaP tumor models. OGX-011 is presently in numerous clinical trials. In pre-surgical trials they demonstrated a dose-dependent decrease in clusterin levels in radical prostatectomy tissues. Next, a randomized Phase II trial of Taxotere alone or with OGX-011 revealed a prolongation in overall survival from 16 to 23 months with the combination therapy. In Taxotere recurrent tumors, the re-exposure to docetaxel and OGX-011 had a median survival of 14.7 months compared to <10 months in second line taxanes treatment alone. There was a more durable pain response in the combined treatment group. Serum clusterin was decreased. Hsp27 is another stress-induced chaperone, and its elimination (using OGX-427) delays progression to CRPC in xenografts models. This is now in Phase I-II trial.
Presented by Martin Gleave, MD at the Society for Basic Urologic Research (SBUR)/Society of Urologic Oncology (SUO) joint meeting during the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.
The opinions expressed in this article are those of the UroToday.com Contributing Editor and do not necessarily reflect the viewpoints of the SPU or the American Urological Association.
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