Abstract 751: Preclinical efficacy of the novel PIM inhibitor, JP_11646, in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is often first diagnosed at an advanced stage with a poor prognosis. Current systemic treatment approaches have limited efficacy, pointing to an urgent need to develop novel therapies. Recent studies have shown that inhibition of Pim-2 activity via JP_11646, a novel pan-PIM inhibitor, resulted in decreased anchorage-independent growth of PDAC. The aim of this work is to examine the ability of JP_11646 alone and in combination with gemcitabine to inhibit the growth of pancreatic cancer cells in vitro and in vivo. Cell viability was assessed using the MTS assay in two pancreatic cancer cell lines, MiaPaCa2 and PANC1. Cells were seeded at an average of 5x103 per well on 96-well plates and exposed to JP_11646 in a range of concentrations (0.01 - 5 µM) for 72 hours. Exposure to JP_11646 inhibited PANC1 and MiaPaCa2 cell growth in a dose-dependent manner, with IC50 values of 0.15 µM and 0.054 µM, respectively. For in vivo experiments, SCID mice were implanted subcutaneously with 3x 106 MiaPaCa2 cells. Upon successful establishment of tumors (approximately 100 mm3), animals were randomly divided into groups for drug and control treatments. JP_11646 was given at 5 or 10 mg/kg by intraperitoneal injection (i.p. injection) once a day for 5 consecutive days from Monday to Friday for a total of six weeks. Gemcitabine i.p. was given at 45 mg/kg in combination treatment or 90 mg/kg as a single agent twice a week every Monday and Friday for a total of six weeks. In a dose-dependent manner, JP_11646 at 5 and 10 mg/kg significantly suppressed the growth of the pancreatic xenograft by 36% and 77% respectively, compare with control PBS treatment in SCID mice. Moreover, the combination of JP-11646 5 mg/kg and gemcitabine 45 mg/kg resulted in a greater tumor inhibition (83%) than either single agent alone [JP_11646 5 mg/kg (36%) or gemcitabine 90 mg/kg (69%)]. Taken together, our results suggest that JP_11646 is a potent inhibitor of pancreatic cancer growth with equivalent efficacy to the maximum tolerated dose of gemcitabine, and is synergistic in combination with gemcitabine. Citation Format: Yi Ding, Vun-Sin Lim, Carmen M. Baldino, Justin Caserta, Yvonne Flanders, Stephane Dumas, Gerald Fetterly, Alex A. Adjei. Preclinical efficacy of the novel PIM inhibitor, JP_11646, in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphi