Targeting Cell Survival Genes Using Antisense Oligonucleotides to Improve Chemo- and Hormonal-Therapies in Prostate Cancer

Abstract

Androgen withdrawal remains the most effective form of systemic therapy for men with advanced prostate cancer, with symptomatic and/or objective response rates in 80% of patients. Unfortunately, progression to androgen-independent (AI) disease occurs within a few years and is the main obstacle to improving survival and quality of life in men with advanced prostate cancer. Novel therapeutic strategies targeting the molecular basis of androgen- and chemotherapy-resistance of prostate cancer are needed because hormone-refractory prostate cancer (HRPC) historically has responded poorly to cytotoxic chemotherapy. Results of recent phase II studies using taxane-based combinations have demonstrated high objective response rates in patients with measurable disease, as well as high rates of prostate-specific antigen (PSA) decline. Phase III trials are underway to confirm these results. Another strategy being investigated to improve outcomes in advanced prostate cancer involves targeting genes, which are activated by either androgen withdrawal or chemotherapy, to delay or prevent the emergence of androgen independence. Targeting genes that are upregulated after chemotherapy or androgen withdrawal (e.g. Bcl-2, clusterin, cathepsins, Bcl-xL), which function to prevent castration-induced apoptosis or activate alternative growth factor pathways, may enhance tumor cell death, prolong time to overt recurrence and ultimately prolong survival.