Small Molecule Therapeutics Enhancement of Nab-Paclitaxel Antitumor Activity through Addition of Multitargeting Antiangiogenic Agents in Experimental Pancreatic Cancer

Nanoparticle albumin–bound paclitaxel (nab-paclitaxel, NPT) has recently shown efficacy in pancreatic ductal adenocarcinoma (PDAC). Targeting tumor angiogenesis is a sensible combination therapeutic strategy for cancer, including PDAC. We tested the hypothesis that NPT response in PDAC can be enhanced by the mechanistically different antiangiogenic agents bevacizumab (Bev) or sunitinib (Su), despite its inherently increased tumor penetration and drug delivery. Compared with controls (19 days), median animal survival was increased after NPT therapy (32 days, a 68% increase, P1⁄4 0.0008); other regimens with enhanced survival were NPTþBev (38 days, a 100% increase, P 1⁄4 0.0004), NPTþSu (37 days, a 95% increase, P 1⁄4 0.0004), and NPTþBevþSu (49 days, a 158% increase, P 1⁄4 0.0001) but not bevacizumab, sunitinib, or BevþSu therapy. Relative to controls (100 22.8), percentage net local tumor growth was 28.2 23.4 with NPT, 55.6 18 (Bev), 38.8 30.2 (Su), 11 7.2 (BevþSu), 32.8 29.2 (NPTþBev), 6.6 10.4 (NPTþSu), and 13.8 12.5 (NPTþBevþSu). Therapeutic effects on intratumoral proliferation, apoptosis,microvessel density, and stromal density correspondedwith tumorgrowth inhibitiondata. InAsPC-1PDACcells,NPT IC50was reduced>6-fold by the addition of sunitinib (IC25) but not by bevacizumab. In humanumbilical vein endothelial cells (HUVEC), NPT IC50 (82 nmol/L) was decreased to 41 nmol/L by bevacizumab and to 63 nmol/L by sunitinib. In fibroblast WI-38 cells, NPT IC50 (7.2 mmol/L) was decreased to 7.8 nmol/L by sunitinib, but not by bevacizumab. These findings suggest that the effects of one of the most active cytotoxic agents against PDAC, NPT, can be enhanced with antiangiogenic agents, which clinically could relate to greater responses and improved antitumor results. Mol Cancer Ther; 13(5); 1–12. 2014 AACR.