Efficacy of the Hsp90 Inhibitors in Prostate Cancer Therapy

Prostate cancer is a disease of aging and the second leading cause of death in men in the United States. A distinctive characteristic of prostate tumors is their dependence on androgen for development, growth and survival. The molecular chaperone Heat Shock Protein-90 (Hsp90) is involved in the stability of a number of protein targets including androgen receptor (AR). Preclinical data demonstrates Hsp90 inhibition to be an effective therapy for inhibiting prostate cancer cells in culture as well as in animal xenograft models. Two newgeneration Hsp90 inhibitors, ganetespib and AT13387, are currently being evaluated as single or combinational therapies in the clinic for castrate resistant prostate cancer (CRPC). While clinical signs of antitumor activity have been observed with new-generation HSP90 inhibitors, these drugs are likely to be most effective when used as part of combination treatments. This review highlights how inhibition of Hsp90 combined with specific secondary targets including Wee1, Hsp27, ERK and mTOR displays enhanced inhibitory effects in pre-clinical models. One clinical benefit of co-inhibition is the targeting of multiple signaling pathways. In addition, the variety of proposed combination therapies allows for latitude in selecting a secondary target, potentially tailoring therapies to specific patient populations.