Abstract 3693: Modeling VEGF dynamics in cancer: An evolutionary game theoretic approach
Authors: Ranjini Bhattacharya, Anuraag Bukkuri, Joel S. Brown
Journal: Cancer Research (2025)

Abstract Cancer cells in rapidly growing tumors often experience nutrient deprivation and hypoxia. They adapt by upregulating pro-angiogenic factors such as VEGF, which promote blood vessel formation within the tumor. Targeting angiogenesis, therefore, aims to starve cancer cells and inhibit tumor growth. This was the driving principle behind the development of anti-angiogenics like bevacizumab and sunitinib. While anti-angiogenics have shown modest improvements in progression-free survival, patients often relapse within the first year of treatment. This underscores the need to understand “why” and “how” VEGF expression evolves in cancer to better inform therapy. Empirical, conceptual, and mathematical models of angiogenesis often assume that VEGF expression by cancer cells represents cooperative behavior towards a shared public good. To evaluate this assumption, we develop an evolutionary game theoretic model to explore how nutrient sharing among cancer cells influences VEGF expression. We find that habitats with high nutrient sharing—where nutrients redirected from blood vessels are evenly distributed among cells—support larger cell population sizes. In contrast, in habitats with low nutrient sharing—where nutrients are distributed in proportion to each cell’s investment in VEGF—cells over-invest in VEGF expression in an attempt to outcompete their neighbors. Individual cancer cells are incentivized to increase VEGF expression not to enhance overall blood supply but to pre-empt the blood supply that otherwise would have gone to others. This over-expression of VEGF comes at the cost of lower cell population sizes. This phenomenon, where individual cells prioritize their own fitness over collective welfare, is known as the tragedy of the commons (TOC). Using the model we evaluate the efficacy of different dosing regimens of anti-angiogenics, glucose transporter (GLUT) inhibitors, and chemotherapy. We find that the TOC diminishes the effectiveness of therapy in habitats with proportional nutrient sharing. Moreover, anti-angiogenic drugs that neutralize VEGF are ineffective at controlling the tumor size. Instead, combining anti-angiogenic drugs with GLUT inhibitors shows greater promise. We are using patient-derived histology samples to observe these trends ex vivo and validate the relevance of our findings in a clinical setting. Our modeling efforts highlight: 1) how mathematical models can provide fresh insights into well-studied biological phenomena, 2) how testing alternative hypotheses about the interactions in the tumor microenvironment is important, and 3) how understanding cancer cell traits as adaptations to selective pressures in the tumor microenvironment aids in developing effective therapeutic strategies. Citation Format: Ranjini Bhattacharya, Anuraag Bukkuri, Joel S. Brown. Modeling VEGF dynamics in cancer: An evolutionary game theoretic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3693.