Abstract 3491: Enhancing nab-paclitaxel antitumor activity through addition of BMS-754807, a small-molecule inhibitor of IGF-1R/IR, in experimental pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, and is expected to become the second-leading cause of cancer death by 2030. Gemcitabine, the standard of care agent over the past 16 years, has limited clinical benefits. Recently, nab-paclitaxel has shown greater efficacy against advanced PDAC in combination with gemcitabine. Our lab has demonstrated superior antitumor activity of nab-paclitaxel compared with gemcitabine or docetaxel in preclinical PDAC studies. Insulin like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC and correlate with aggressive tumor phenotype and poor prognosis indicating that the IGF system is an important therapeutic target in PDAC patients. BMS-754807, a small molecule inhibitor of IGF-type 1 receptor (IGF-1R) and insulin receptor (IR), has shown efficacy in PDAC. We evaluated combination treatment benefits of nab-paclitaxel with BMS-754807 in experimental PDAC. In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Heterotopic tumor growth and animal survival experiments were performed in murine xenografts. In vitro analysis of four PDAC cell lines (AsPC-1, BxPC-3, MIA PaCa-2, Panc-1) revealed that single agent nab-paclitaxel and BMS-754807 both inhibited cell proliferation in a dose-dependent manner. To evaluate the combination treatment benefits of nab-paclitaxel and BMS-754807, the IC25 dose of BMS-754807 was combined with increasing doses of nab-paclitaxel. Addition of BMS-754807 decreased the nab-paclitaxel IC50 from 7.2 μM to 490 nM for AsPC-1, 430 nM to 50 nM for BxPC-3, 740 nM to 540 nM for MIA PaCa-2, and 690 nM to 280 nM for Panc-1 cell lines. These data suggest that BMS-754807 combines well with nab-paclitaxel and efficiently decreases the nab-paclitaxel IC50 in PDAC cell lines. In a heterotopic AsPC-1 PDAC model, relative to controls (100±21.3), percent net local tumor growth was 17.1±21.1 with nab-paclitaxel (p = 0.002), 37.6±16.2 with BMS-754807 (p = 0.01) and 0.76±9.1 with nab-paclitaxel plus BMS-754807 (p = 0.0002). In Panc-1 subcutaneous xenografts, compared with controls (100±31.5), percent net tumor growth was 7.8±27.2 with nab-paclitaxel (p = 0.002), 40.2±24.1 with BMS-754807 (p = 0.02) and -29.7±16.8 with nab-paclitaxel plus BMS-754807 (p = 0.0001). In an animal survival study, median animal survival was increased compared to controls (21 days) after nab-paclitaxel therapy (40 days, a 90% increase, p = 0.002), BMS-754807 therapy (27 days, a 29% increase, p = 0.01), and nab-paclitaxel plus BMS-754807 therapy (47 days, a 124% increase, p = 0.005). These results highlight measurable antitumor activity of BMS-754807 in experimental PDAC and support the potential of BMS-754807 in combination with nab-paclitaxel as promising targeted therapy for clinical pancreatic cancer therapy. Citation Format: Niranjan Awasthi, Margaret A. Schwarz, Roderich E. Schwarz. Enhancing nab-paclitaxel antitumor activity through addition of BMS-754807, a small-molecule inhibitor of IGF-1R/IR, in experimental pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3491. doi:10.1158/1538-7445.AM2015-3491