Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and Canine Mast Cell Tumors.
London CA, Acquaviva J, Smith DL, Sequeira M, Ogawa LS, Gardner HL, Bernabe LF, Bear MD, Bechtel SA, Proia DA
Clin Cancer Res 24 6396-6407 12/15/2018
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: 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.
RESULTS: Continuous HSP90 inhibition led to durable destabilization of client proteins
CONCLUSIONS: These data provide further evidence that prolonged HSP90i exposure improves biologic activity through sustained downregulation of client proteins.