Abstract 2740: Antitumor activity of BMS-754807, a small molecule inhibitor of insulin-like growth factor-1 receptor / insulin receptor, in combination with gemcitabine in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies characterized by late clinical presentation, rapid local and metastatic progression and high resistance to conventional therapies. Gemcitabine, an approved treatment for PDAC, has limited clinical benefits. The insulin-like growth factor (IGF) type 1 receptor (IGF-1R) has shown to be expressed in many human cancers including PDAC. The present study evaluated the therapeutic potential of BMS-754807, a small molecule inhibitor of IGF-1R and insulin receptor (IR), alone and in combination with gemcitabine, in experimental PDAC. The human PDAC cell lines were grown in RPMI 1640 medium supplemented with 10% FBS. In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Ki67 and TUNEL staining were used to detect intratumoral proliferation and apoptosis. PDAC cell lines AsPC-1, BxPC-3, Mia PaCa-2 and Panc-1 expressed IGF-1R and phospho-IGF-1R proteins. BMS-754807 and gemcitabine inhibited in vitro cell proliferation of PDAC cell lines; the combination of BMS-754807 with gemcitabine had additive effects. IC25 concentrations of BMS-754807 decreased gemcitabine IC50 from 9.7 μM to 75 nM for AsPC-1, from 3 μM to 70 nM for Panc-1, from 72 nM to 16 nM for Mia PaCa-2 and from 28 nM to 16 nM for BxPC-3 cells, respectively. BMS-754807 caused a significant decrease in phospho-IGF-1R and phospho-AKT proteins in AsPC-1 and Panc-1 cells. BMS-754807 and gemcitabine caused an increase in apoptosis-related PARP-1 and caspase-3 cleavage with additive effects in combination. Compared with controls, in vivo net tumor growth inhibition in BMS-754807, gemcitabine and BMS-754807+gemcitabine groups was 59 percent (p=0.05), 35 percent (p=0.02) and 94 percent (p=0.0007), respectively. Effects on intratumoral proliferation and apoptosis after BMS-754807 and gemcitabine treatments corresponded directly with tumor growth inhibition data. BMS-754807 also caused a decrease in phospho-IGF-1R and phospho-AKT in tumor tissue lysates. Median animal survival (Controls: 21 days) after BMS-754807 was 27 days (p=0.03 versus control), after gemcitabine group 28 days (p=0.05 versus control) and in the BMS-754807+gemcitabine combination group 41 days (p=0.007 versus control and p=0.02 versus gemcitabine or BMS-754807 monotherapy). BMS-754807 has strong antitumor activity in experimental PDAC, and it significantly improves gemcitabine response. These results support the potential of BMS-754807-induced mechanisms for clinical PDAC therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2740. doi:1538-7445.AM2012-2740