Abstract 1043: Enhancing cytotoxic chemotherapy effects by nintedanib in gastric cancer preclinical models

Abstract

Abstract Background: Gastric adenocarcinoma (GAC) remains the 3rd most common cause of cancer mortality in the world. Systemic chemotherapy is a preferred treatment option for advanced and recurrent GAC, but response rates and survival extension remain limited. Tumor angiogenesis plays a critical role in GAC growth, invasion and metastasis. In this study, we determined the antitumor efficacy of nintedanib, a potent triple angiokinase inhibitor for VEGFR-1/2/3, PDGFR-α/β and FGFR-1/2/3, alone or in combination with chemotherapy, in preclinical models of GAC. Methods: Animal survival and tumor growth studies were performed in 4-6 week-old female NOD/SCID mice with human GAC cell xenografts (MKN-45, KATO-III, SNU-5). The mechanistic evaluation involved Immunohistochemistry and Immunoblot analyses of subcutaneous tumors. In vitro cell viability assays were performed using colorimetric WST-1 reagent. Results: In MKN-45 cell-derived peritoneal dissemination xenografts, animal survival was improved by nintedanib (33%), docetaxel (100%) or irinotecan (181%), while oxaliplatin, 5-FU and epirubicin had no effect. The addition of nintedanib to docetaxel (157%) or irinotecan (214%) led to a further extension in animal survival. In KATO-III cell-derived xenografts carrying FGFR2 gene amplification, nintedanib monotherapy extended survival much more (209%). Docetaxel and irinotecan effects were again further enhanced by nintedanib. In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel or irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%). The addition of nintedanib to all chemotherapy groups demonstrated a further reduction in tumor growth. Subcutaneous tumor analysis revealed that nintedanib attenuated tumor cell proliferation, reduced tumor vasculature and increased tumor cell death. Nintedanib (10 μM) inhibited in vitro cell proliferation of mutationally different GAC cells by 25% (MKN-45), 75% (KATO-III) or 82% (SNU-5), and confirmed additive inhibitory effects in combinations with chemotherapy agents. Conclusion: Nintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. Combination regimens with nintedanib have the potential for improving clinical GAC therapy. Citation Format: Niranjan Awasthi, Margaret A. Schwarz, Frank Hilberg, Roderich E. Schwarz. Enhancing cytotoxic chemotherapy effects by nintedanib in gastric cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1043.