Cancer treatment scheduling and dynamic heterogeneity in social dilemmas of tumour acidity and vasculature

TL;DR

This paper models tumor heterogeneity and treatment timing using evolutionary game theory, revealing distinct dynamic regimes and emphasizing the importance of treatment order and timing for effective cancer therapy.

Contribution

It introduces a double goods game model to analyze tumor heterogeneity involving glycolytic and angiogenic traits, highlighting new dynamic regimes and treatment implications.

Findings

Identifies three tumor phenotypic regimes: glycolytic, angiogenic, and polyclonal.

Demonstrates dynamic heterogeneity can persist with linear goods, unlike previous models.

Suggests treatment timing and order critically influence therapy outcomes.

Abstract

Background: Tumours are diverse ecosystems with persistent heterogeneity in various cancer hallmarks like self-sufficiency of growth factor production for angiogenesis and reprogramming of energy-metabolism for aerobic glycolysis. This heterogeneity has consequences for diagnosis, treatment, and disease progression. Methods: We introduce the double goods game to study the dynamics of these traits using evolutionary game theory. We model glycolytic acid production as a public good for all tumour cells and oxygen from vascularization via VEGF production as a club good benefiting non-glycolytic tumour cells. This results in three viable phenotypic strategies: glycolytic, angiogenic, and aerobic non-angiogenic. Results: We classify the dynamics into three qualitatively distinct regimes: (1) fully glycolytic, (2) fully angiogenic, or (3) polyclonal in all three cell types. The third regime allows for dynamic heterogeneity even with linear goods, something that was not possible in prior public good models that considered glycolysis or growth-factor production in isolation. Conclusion: The cyclic dynamics of the polyclonal regime stress the importance of timing for anti-glycolysis treatments like lonidamine. The existence of qualitatively different dynamic regimes highlights the order effects of treatments. In particular, we consider the potential of vascular renormalization as a neoadjuvant therapy before follow up with interventions like buffer therapy.