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

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC 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