Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors.

Abstract

STA-1474, prodrug of the heat shock protein 90 inhibitor (HSP90i) ganetespib, previously demonstrated activity in canine preclinical models of cancer; interestingly, prolonged infusions were associated with improved biologic activity. The purpose of this study was to identify the ideal treatment schedule for HSP90i in preclinical models of KIT-driven malignancies and in dogs with spontaneous mast cell tumors (MCT), where KIT is a known driver. <i>In vitro</i> and murine xenograft experiments and clinical studies in dogs with MCTs were used to define the effects of HSP90i-dosing regimen on client protein downregulation and antitumor activity. Continuous HSP90 inhibition led to durable destabilization of client proteins <i>in vitro</i>; however, transient exposure required >10× drug for comparable effects. <i>In vivo</i>, KIT was rapidly degraded following a single dose of HSP90i but returned to baseline levels within a day. HSP90 levels increased and stabilized 16 hours after HSP90i and were not elevated following a subsequent near-term exposure, providing a functional pool of chaperone to stabilize proteins and a means for greater therapeutic activity upon HSP90i reexposure. HSP90i administered on days 1 and 2 (D1/D2) demonstrated increased biologic activity compared with D1 treatment in KIT or EGFR-driven murine tumor models. In a trial of dogs with MCT, D1/D2 dosing of HSP90i was associated with sustained KIT downregulation, 50% objective response rate and 100% clinical benefit rate compared with D1 and D1/D4 schedules. These data provide further evidence that prolonged HSP90i exposure improves biologic activity through sustained downregulation of client proteins.