Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models

Frontiers in Oncology

Oncology

Frank Hilberg¹  Quinn Kaurich²  Niranjan Awasthi³  Changhua Zhang⁴  Margaret A. Schwarz⁵  Roderich E. Schwarz⁶ 

[1] Department of Pharmacology, Boehringer Ingelheim Regional Center Vienna, Vienna, Austria;Department of Surgery, Indiana University School of Medicine, South Bend, IN, United States;Department of Surgery, Indiana University School of Medicine, South Bend, IN, United States;Harper Cancer Research Institute. University of Notre Dame, Notre Dame, IN, United States;Digestive Diseases Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China;Harper Cancer Research Institute. University of Notre Dame, Notre Dame, IN, United States;Department of Pediatrics, Indiana University School of Medicine, South Bend, IN, United States;Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States;

关键词: gastric cancer;    chemotherapy;    nintedanib;    angiogenesis;    combination therapy;   

DOI  :  10.3389/fonc.2023.1145999

 received in 2023-01-16, accepted in 2023-04-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundGastric adenocarcinoma (GAC) is the fourth leading cause of cancer death worldwide. Systemic chemotherapy is a preferred treatment option for advanced and recurrent GAC, but response rates and survival prolongation remain limited. Tumor angiogenesis plays a critical role in GAC growth, invasion and metastasis. We investigated 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.MethodsAnimal survival studies were performed in peritoneal dissemination xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and KATO-III. Tumor growth inhibition studies were performed in subcutaneous xenografts in NOD/SCID mice using human GAC cell lines MKN-45 and SNU-5. The mechanistic evaluation involved Immunohistochemistry analyses in tumor tissues obtained from subcutaneous xenografts. In vitro cell viability assays were performed using a colorimetric WST-1 reagent.ResultsIn MKN-45 GAC cell-derived peritoneal dissemination xenografts, animal survival was improved by nintedanib (33%), docetaxel (100%) and 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 GAC cell-derived xenografts carrying FGFR2 gene amplification, nintedanib extended survival by 209%. Again, the addition of nintedanib further enhanced the animal survival benefits of docetaxel (273%) and irinotecan (332%). In MKN-45 subcutaneous xenografts, nintedanib, epirubicin, docetaxel and irinotecan reduced tumor growth (range: 68-87%), while 5-FU and oxaliplatin had a smaller effect (40%). Nintedanib addition to all chemotherapeutics 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.ConclusionNintedanib showed notable antitumor efficacy and significantly improved taxane or irinotecan chemotherapy responses. These findings indicate that nintedanib, alone and in combination with a taxane or irinotecan, has the potential for improving clinical GAC therapy.

【 授权许可】

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Copyright © 2023 Awasthi, Schwarz, Kaurich, Zhang, Hilberg and Schwarz