Accession Number:

ADA625414

Title:

Clinical Development of Gamitrinib, a Novel Mitochondrial-Targeted Small Molecule Hsp90 Inhibitor

Descriptive Note:

Annual rept. 1 Sep 2014-31 Aug 2015

Corporate Author:

WISTAR INST OF ANATOMY AND BIOLOGY PHILADELPHIA PA

Personal Author(s):

Report Date:

2015-09-01

Pagination or Media Count:

49.0

Abstract:

The past funding cycle of the present award has supported important advances in each of the milestones and specific tasks set forth in the original SOW. Work supported by the present award focused on three directions with the overarching goal of completing the original specific aim 2 of the application. First, we continued the preclinical characterization of Gamitrinib as a unique anticancer agent. Published in the premiere, peer-reviewed literature JNCI, PNAS and Sci Signal, these studies demonstrated that the combination of Gamitrinib plus small molecule inhibitors of PI3KAktmTOR pathway currently in the clinic delivered potent and synergistic anticancer activity in preclinical models i, suppressed adaptive mitochondrial reprogramming of enhanced tumor cell survival ii and blocked a novel pathway of prostate cancer invasion and metastasis supported by mitochondrial bioenergetics at the cortical cytoskeleton iii. Second, an initial non- GLP 7-day repeated dose toxicology study in rats using Gamitrinib formulated in the original formulation 75 DMSO- 25 PBS demonstrated toxicity at the highest dose used of 6 mgkgdaily after 4 repeated i.v. doses. Third, and in light of these initial results, we identified and characterized a novel, non-DMSO-based emulsion of Gamitrinib, which retained anticancer activity. This novel emulsion-based formulation of Gamitrinib will be used in the next budget cycle for new non-GLP repeated-dose toxicology in suitable animal species, as anticipated in the original SOW.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE