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Consecutive Day HSP90 Inhibitor Administration Improves Efficacy in Murine Models of KIT-Driven Malignancies and

Cheryl A London1,2, Jaime Acquaviva3, Donald L Smith3

  • 1Departments of Veterinary Biosciences and Clinical Sciences, The Ohio State University, Columbus, Ohio. cheryl.london@tufts.edu.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 2, 2018
PubMed
Abstract

Insights

Prolonged heat shock protein 90 inhibition (HSP90i) improves cancer treatment by sustaining client protein downregulation. Dosing HSP90i on consecutive days enhanced anti-tumor activity in preclinical models and canine mast cell tumors.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Biology

Background:

  • STA-1474, a prodrug of heat shock protein 90 inhibitor (HSP90i) ganetespib, showed promise in canine cancer models.
  • Prolonged infusions of HSP90i were linked to enhanced biological activity.

Purpose of the Study:

  • To determine the optimal treatment schedule for HSP90 inhibitors.
  • To evaluate HSP90i efficacy in preclinical models of KIT-driven cancers and canine mast cell tumors (MCTs).

Main Methods:

  • Utilized in vitro and murine xenograft experiments.
  • Conducted clinical studies in dogs with MCTs.
  • Assessed the impact of HSP90i dosing on client protein downregulation and anti-tumor effects.

Main Results:

  • Continuous HSP90 inhibition achieved durable client protein destabilization in vitro.
  • In vivo, HSP90i administration on days 1 and 2 (D1/D2) showed greater biologic activity than D1 treatment in murine models.
  • In dogs with MCTs, D1/D2 HSP90i dosing resulted in sustained KIT downregulation, a 50% objective response rate, and a 100% clinical benefit rate.

Conclusions:

  • Sustained downregulation of client proteins through prolonged HSP90 inhibition enhances biological activity.
  • The D1/D2 dosing schedule represents a potentially more effective strategy for HSP90i in treating KIT-driven malignancies.

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