TARGETING HSP 27 FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER

摘要

Prostate cancer is the most common cancer in men and the second leading cause of death from cancer in North America. While responsive to androgen ablation in its early stages, prostate cancer eventually becomes castration-resistant (CRPC) and metastasizes, preferentially to bone. Once this happens, the disease carries considerable morbidity and is incurable. Previous work conducted in our laboratory showed that heat shock protein HSP 27, a stress-activated cytoprotective chap-erone, is upregulated after castration and chemotherapy in prostate cancer and associated with metastasis and poor prognosis. HSP 27 acts through an ATP-independent mechanism, making this target less amenable to inhibition by small molecules, and so strategies to inhibit HSP 27 at the gene expression level become appealing. Indeed, known nucleotide sequences of cancer-relevant genes offer the possibility to rapidly design antisense oligonucleotides (ASO) or short interfering RNA (siRNA) for loss-of-function and preclinical proof-of-phnciple studies. We will review antiapoptotic and cell survival pathways regulated by HSP 27 and preclinical studies using antisense therapeutics (OGX-427) to support targeting of HSP 27 in CRPC.