Integrated development of S-Trans,Trans-Farnesylthiosalicyclic acid (FTS,Salisarib) in pancreatic cancer

Abstract

4626 Background: The Ras signaling pathway is a strategic target in pancreas cancer. Prior attempts to block Ras activity by inhibiting farnesyltransferase have been ineffective as escape pathways exist that allow for alternative prenylation of Ras protein. FTS inhibits Ras dependent cell growth by dislodging all Ras isoforms from membrane binding sites. We studied this agent in a pancreas cancer model and in patients with advanced pancreatic cancer. Methods: 14 pancreatic cancer tumors obtained from patients were implanted in nude mice and treated with FTS (40 mg/kg p.o.). Tumor growth inhibition and drug effects in the targeted pathways were determined by Western blot, IHC and gene expression arrays. Patients with treatment naïve advanced pancreas cancer were treated with gemcitabine (Gem) at standard dose/schedule + FTS at doses of 200–800 mg p.o. bid 21 days of a 28 day cycle. Patients were treated until progression or protocol defined DLT. Plasma was collected to characterize PK of FTS and Gem. PBMCs and tissue biopsies pre and post cycle 1 were collected to characterize the effect of Gem + FTS on levels of activated Ras protein. Treatment efficacy was assessed every other cycle. Results: In a pancreas cancer xenograft model FTS inhibited tumor growth in 15% of cases and resulted in downregulation of Ras protein levels in tumor tissues and of genes in the cell cycle and Ras signaling pathway. In the clinical trial, a total of 12 patients have been treated to date. No PK interaction has been identified. Of the 9 evaluable patients, the most frequent reported FTS related adverse event has been diarrhea but not dose limiting. Two patients (one in first 2 cohorts) were removed from study secondary to persistent Gr 3 neutropenia related to Gem. Following cycle 1, 6 patients had a decrease in CA19–9 (range -16% to -98%) with 1 partial response and 7 patients with stable disease with FTS induced Ras downregulation. Conclusions: FTS effectively modulates Ras protein level in pancreas cancer xenografts. The combination of Gem +FTS appears safe with no PK interaction and appears to demonstrate clinical and PD activity. An expanded cohort is underway with Gem + FTS at the 800 mg bid. PBMCs and tissue biopsies to characterize the effect of Gem + FTS on levels of activated Ras protein are underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Averion International Corp Averion International Corp. of which Concordia Pharmaceuticals is a client of, Concordia Pharmaceuticals, Inc. Concordia Pharmaceuticals, Inc.