Enhancement of Nab-paclitaxel Antitumor Activity through Addition of Multitargeting Antiangiogenic Agents in Experimental Pancreatic Cancer

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 nab-paclitaxel 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 to controls (19 days) median animal survival was increased after NPT therapy (32 days, a 68% increase, p<0.0008); other regimens with enhanced survival were NPT+Bev (38 days, a 100% increase, p<0.0004), NPT+Su (37 days, a 95% increase, p<0.0004) and NPT+Bev+Su (49 days, a 158% increase, p<0.0001) but not Bev, Su or Bev+Su therapy. Relative to controls (100±22.8), percent net local tumor growth was 28.2±23.4 with NPT, 55.6±18 (Bev), 38.8±30.2 (Su), 11±7.2 (Bev+Su), 32.8±29.2 (NPT+Bev), 6.6±10.4 (NPT+Su) and 13.8±12.5 (NPT+Bev+Su). Therapeutic effects on intratumoral proliferation, apoptosis, microvessel density and stromal density corresponded with tumor growth inhibition data. In AsPC-1 PDAC cells, nab-paclitaxel IC50 was reduced >6-fold by addition of sunitinib (IC25) but not by bevacizumab. In HUVEC endothelial cells, nab-paclitaxel IC50 (82 nM) was decreased to 41 nM by bevacizumab and to 63 nM by sunitinib. In fibroblast WI-38 cells, nab-paclitaxel IC50 (7.2 μM) was decreased to 7.8 nM by sunitinib, but not by bevacizumab. These findings suggest that the effects of one of the most active cytotoxic agents against PDAC, nab-paclitaxel, can be enhanced with antiangiogenic agents, which clinically could relate to greater responses and improved antitumor results.

http://mct.aacrjournals.org/content/early/2014/03/06/1535-7163.MCT-13-0361.abstract

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