Abstract 2208: Targeted inhibition of FGF/PDGF/VEGF signaling enhances nanoparticle taxane response in preclinical gastric cancer models

Abstract

Abstract Background: Gastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Most available systemic chemotherapy options for advanced GAC have limited efficacy. Nab-paclitaxel (NPT), a nanoparticle albumin-bound taxane formulation, has shown significant activity in preclinical GAC studies. Overexpression of multiple growth factors and their receptors such as FGF/FGFR, PDGF/PDGFR and VEGF/VEGFR, promote angiogenesis in several cancers including GAC that leads to tumor progression and metastasis. Dovitinib is a small molecule RTK inhibitor that potentially inhibits the activity of FGFR, PDGFR and VEGFR. We evaluated the antitumor efficacy of dovitinib and its ability to enhance nab-paclitaxel response in preclinical GAC models. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and Immunoblotting. In vivo tumor growth and animal survival studies were performed in NOD/SCID mice using human GAC MKN-45 cells. Results: Nab-paclitaxel and dovitinib had in vitro growth inhibitory effect on several GAC associated cell lines tested, with additive effects in combination. Immunoblot analysis revealed that dovitinib treatment caused a decrease in the expression of phospho-FGFR, phospho-AKT, phospho-ERK; and an increase in the expression of apoptosis-related proteins cleaved PARP-1 and cleaved caspase-3. Nab-paclitaxel activity correlated with the increased expression of phospho-stathmin. In subcutaneous GAC xenografts, NPT and dovitinib demonstrated inhibition in tumor growth, while NPT+dovitinib had an additive effect. Net tumor growth was 533.7 mm3 in controls, 394.8 mm3 after oxaliplatin, 135.8 mm3 after NPT, 128 mm3 after dovitinib, 98.9 mm3 after oxaliplatin+dovitinib and -41.8 mm3 (tumor regression) after NPT+dovitinib. Tumor tissue analysis revealed that dovitinib reduced tumor vasculature, while nab-paclitaxel reduced tumor cell proliferation. In a peritoneal dissemination model, animal survival compared to controls (23 days) remained unchanged after monotherapy with oxaliplatin (24 days) or dovitinib (25 days) but increased significantly after NPT monotherapy (42 days, a 83% increase). Combination of dovitinib with NPT exhibited a further increase in animal survival (66 days, a 187% increase), while the combination of dovitinib with oxaliplatin had no survival benefit (25 days). Conclusion: These findings demonstrate that the antitumor effect of nab-paclitaxel can be significantly enhanced by the FGFR/PDGFR/VEGFR pathway inhibitor dovitinib in preclinical GAC models. The data support the clinical relevance of this therapeutic combination for advanced GAC patients. Citation Format: Niranjan Awasthi, Kate Crawford, Erin Bontrager, Sazzad Hassan, Urs von Holzen, Margaret A. Schwarz, Roderich E. Schwarz. Targeted inhibition of FGF/PDGF/VEGF signaling enhances nanoparticle taxane response in preclinical gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2208.