Many strategies used to kill
cancer cells induce stress-responses that activate survival pathways to promote emergence of a treatment resistant phenotype. Secretory
clusterin (sCLU) is a stress-activated cytoprotective chaperone up-regulated by many varied anticancer
therapies to confer treatment resistance when overexpressed. sCLU levels are increased in several treatment recurrent
cancers including castrate resistant
prostate cancer, and therefore sCLU has become an attractive target in
cancer therapy. sCLU is not druggable with small molecule inhibitors, therefore
nucleotide-based strategies to inhibit sCLU at the
RNA level are appealing. Preclinical studies have shown that
antisense oligonucleotide (ASO) or
siRNA knockdown of sCLU have preclinical activity in combination with
hormone- and
chemotherapy. Phase I and II clinical trial data indicate that the second generation ASO,
custirsen (OGX-011), has
biologic and clinical activity, suppressing sCLU expression in
prostate cancer tissues by more than 90%. A randomized study comparing
docetaxel-
custirsen to
docetaxel alone in men with castrate resistant
prostate cancer reported improved survival by 7 months from 16.9 to 23.8 months. Strong preclinical and clinical proof-of-principle data provide rationale for further study of sCLU inhibitors in randomized phase III trials, which are planned to begin in 2010.