Clinical Development of Gamitrinib, a Novel Mitochondrial-Targeted Small Molecule Hsp90 Inhibitor
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 PI3K/Akt/mTOR 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 mg/kg/daily 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- ADA625414
Entities
People
- Dario C Altieri
Organizations
- Wistar Institute