Consecutive day HSP90 inhibitor administration improves efficacy in murine models of KIT-driven malignancies and canine mast cell tumors

Purpose: 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. Experimental Design: In vitro 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 anti-tumor activity. Results: Continuous HSP90 inhibition led to durable destabilization of client proteins in vitro; however transient exposure required >10X drug for comparable effects. In vivo, 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 re-exposure. HSP90i administered on Days 1 and 2 (D1/D2) demonstrated increased biologic activity compared to 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 to D1 and D1/D4 schedules. Conclusions: These data provide further evidence that prolonged HSP90i exposure improves biologic activity through sustained downregulation of client proteins.

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