Abstract 2071: Addition of antiangiogenic agents enhances nab-paclitaxel antitumor activity in experimental pancreatic cancer.

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by early tissue invasion and metastasis, complex desmoplastic stromal response, and high resistance to systemic therapies. Nanoparticle albumin-bound (nab) paclitaxel (NPT) has the potential for pharmacodynamic advantages over conventional taxanes and has shown efficacy as mono- and combination therapeutic agent in several malignancies including pancreatic, lung and ovarian cancer. We evaluated the combination treatment benefits of nab-paclitaxel with the antiangiogenic agents bevacizumab (Bev) and sunitinib (Su) in experimental pancreatic cancer. 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. Intratumoral proliferation and apoptosis were evaluated via Ki67 and TUNEL staining. Nab-paclitaxel displayed higher in vitro antiproliferative activity as a single agent in pancreatic cancer compared with gemcitabine or the polysorbate-based taxane docetaxel. In AsPC-1 PDAC cells, nab-paclitaxel IC50 was reduced more than 6-fold by an IC25 dose of sunitinib (500 nM) but not by bevacizumab (10 μg/ml). In endothelial cells HUVEC, nab-paclitaxel IC50 (82 nM) was decreased to 41 nM by bevacizumab (10 μg/ml) and to 63 nM by sunitinib (100 nM). In fibroblast WI-38 cells, nab-paclitaxel IC50 (7.2 μM) was decreased to 7.8 nM by the IC25 dose of sunitinib (2.5 μM), but no significant decrease was observed by bevacizumab (50 μg/ml) addition. Nab-paclitaxel increased stathmin phosphorylation and decreased tubulin expression in vitro. In a subcutaneous murine xenograft model, net tumor growth inhibition in NPT, Bev, Su, Bev+Su, NPT+Bev, NPT+Su and NPT+Bev+Su was 72, 44, 61, 89, 67, 93 and 86 percent. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. In tumor tissue lysates, nab-paclitaxel caused an increase in stathmin phosphorylation but no change in tubulin expression. In an intraperitoneal murine xenograft model, compared to controls (median survival: 19 days), animal survival increased after nab-paclitaxel (32 days, p=0.0008) but not after antiangiogenic therapy with Bev (21 days), Su (24 days) or Bev+Su (22 days; for all: p=NS). Animal survival was further increased by the combination treatment of nab-paclitaxel with bevacizumab and sunitinib, with a median survival of 38, 37 and 49 days in NPT+Bev (p=0.03 vs. NPT), NPT+Su (p=0.174 vs. NPT) and NPT+Bev+Su (p=0.001 vs. NPT) groups, respectively. Nab-paclitaxel has strong antitumor activity as a single agent in this model of experimental pancreatic cancer. Nab-paclitaxel effects were further enhanced by addition of the antiangiogenic agents bevacizumab and sunitinib. These findings strongly support the potential of nab-paclitaxel based combination strategies for clinical PDAC therapy. Citation Format: Niranjan Awasthi, Changhua Zhang, Stefan Hinz, Margaret A. Schwarz, Roderich E. Schwarz. Addition of antiangiogenic agents enhances nab-paclitaxel antitumor activity in experimental pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2071. doi:10.1158/1538-7445.AM2013-2071