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

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[Technical Report, Annual Report]

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Heat shock proteins Hsp40, Hsp70 and Hsp90 are molecular chaperones required for stabilizationactivation 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 percent 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 Hsp40Hsp70Hsp90 chaperone axis for activity, the chaperone requirements of ARv are not known. BecauseHsp90 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 onHsp40Hsp70 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.


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  • Medicine and Medical Research

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[A, Approved For Public Release]