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

ABSTRACT

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.