Targeting the HSP40/HSP70 Molecular Chaperone Axis as a Novel Treatment Strategy for Castrate-Resistant Prostate Cancer

Heat shock proteins Hsp40, Hsp70 and Hsp90 are molecular chaperones required for stabilization/activation of nuclear receptors, including full-length androgen receptor (AR) and glucocorticoid receptor (GR). Although ligand-binding domain (LBD) targeted (LBDT) therapy initially inhibits AR function and improves patient survival, this treatment almost invariably leads to emergence of castration-resistant prostate cancer (CRPC). CRPC is frequently characterized by elevated expression of alternative nuclear receptors able to at least partially maintain the AR transcriptional program. These alternative receptors include GR, which is expressed in approximately 30% of LBDT therapy-sensitive prostate cancer, but is expressed at a much higher frequency in CRPC and in those patients with a poor response to LBDT therapy. Additionally, elevated expression of a number of constitutively active AR splice variants lacking the LBD (ARv, particularly ARv7, which correlates with poor prognosis, reduced survival, and resistance to LBDT therapy, and ARv567es) is a frequent occurrence in CRPC. While full length GR and AR depend on the Hsp40/Hsp70/Hsp90 chaperone axis for activity, the chaperone requirements of ARv are not known. Because Hsp90 interacts with the LBD, ARv are insensitive to Hsp90 inhibitors. However, based on strong preliminary data, we believe that ARv, like GR and AR, retain dependence on Hsp40/Hsp70 and we will test this hypothesis using combined biophysical, genetic, biochemical and pharmacological approaches, including novel small molecules able to bind and inhibit both Hsp40 and Hsp70. We envision a synergistic group of studies that will result in a detailed and comprehensive picture of the specific chaperone dependence of these individual nuclear receptors.

Development of Molecular Chaperone Inhibitors for (Re)Sensitization of CRPC to Enzalutamide and Abiraterone and to Synergize with Metabolic Inhibitors

Objective: (1) Improve the solubility and pharmacodynamic properties of previously identified Hsp40 and Hsp70 inhibitors in preparation for Phase I clinical evaluation in CRPC patients. (2) Determine whether these chaperone inhibitors sensitize resistant CRPC to Enz and/or Abi and, if so, by what mechanism(s). (3) Increase our understanding of the role of these chaperones in regulating AR-driven metabolic deregulation, with the goal of identifying novel synergistic combinatorial approaches to target CRPC. Impact: By identifying a chaperone-based approach to inhibit or reverse CRPC resistance to Enz and/or Abi, the current research proposal addresses the dual 2018 PCRP Overarching Challenges of (1) developing treatments that improve the outcomes for men with lethal prostate cancer and (2) better defining the biology of lethal prostate cancer to reduce death. Further, consistent with the mandate of the PCRP Impact Award, a key goal of our research strategy is to position the program for first-in-human clinical evaluation of one or more of these chaperone inhibitors within 5 years after completion of this Award.