Evolutionarily stable anti-cancer therapies by autologous cell defection

M. Archetti

doi:10.1093/emph/eot014

Abstract

Game theory suggests an anti-cancer treatment based on the use of modified cancer cells that disrupt cooperation within the tumor. Cancer cells are harvested from the patient, the genes for the production of essential growth factors are knocked out in vitro and the cells are then reinserted in the tumor, where they lead to its collapse. Current anti-cancer drugs and treatments based on gene therapy are prone to the evolution of resistance, because cancer is a process of clonal selection: resistant cell lines have a selective advantage and therefore increase in frequency, eventually conferring resistance to the whole tumor and leading to relapse. An effective treatment must be evolutionarily stable, that is, immune to the invasion of resistant mutant cells. This study shows how such a treatment can be achieved by autologous cell therapy using modified cancer cells, knocked out for genes coding for diffusible factors like growth factors. The evolutionary dynamics of a population of cells producing diffusible factors are analyzed using a nonlinear public goods game in a structured population in which the interaction neighborhood and the update neighborhood are decoupled. The analysis of the dynamics of the system reveals what interventions can drive the population to a stable equilibrium in which no diffusible factors are produced. A treatment based on autologous knockout cell therapy can be designed to lead to the spontaneous collapse of a tumor, without targeting directly the cancer cells, their growth factors or their receptors. Critical parameters that can make the therapy effective are identified. Concepts from evolutionary game theory and mechanism design, some of which are counterintuitive, can be adopted to optimize the treatment. Although it shares similarities with other approaches based on gene therapy and RNA interference, the method suggested here is evolutionarily stable under certain conditions. This method, named autologous cell defection, can be carried out using existing molecular biology and cell therapy techniques.

Highlights

AND OBJECTIVESThe development of anti-cancer therapies normally begins with the identification of a molecule or pathway that is necessary for the development of the tumor and continues with the design of a method to target that molecule or pathway
Antiangiogenic therapies are a case in point [1]: it has long been known that oxygen concentration decreases with distance from a capillary [2, 3]; this led to the hypothesis that tumors cannot grow without inducing the formation of new blood vessels [4,5,6] and that disrupting neoangiogenesis could be an anti-cancer therapy [7]; the search for the ‘tumor angiogenesis factor’ lead to the identification of VEGF as the primary responsible for neoangiogenesis [8, 9] and the eventual development of a monoclonal antibody targeting VEGF
We focus on the production of growth factors by cancer cells, one of the hallmarks of cancer [23] and we start from the evolutionary game theory of growth factor production

Summary

Introduction

AND OBJECTIVESThe development of anti-cancer therapies normally begins with the identification of a molecule or pathway that is necessary for the development of the tumor and continues with the design of a method to target that molecule or pathway. A humanized variant of this anti-VEGF antibody led to the development of bevacizumab (Avastin; Genentech) [10], which was for a long time Roche’s best selling drug, with revenues in excess of 5 billion USD per year Even such a blockbuster drug can only extend survival for patients with certain types of cancer by a few months on average [11], far from being a cure for cancer. The problem with most current anti-cancer treatments is that cancer is a process of clonal selection within the body on the timescale of an individual’s lifetime [14,15,16,17,18], and mutant cell lines that are resistant to treatments can spread and eventually confer resistance to the whole tumor This is why even the most modern anti-cancer drugs generally lead to relapse after few months, including modern drugs that, like Avastin, target growth factors [11, 19]. Little attention (if any), is devoted to understanding the evolutionary stability of treatments [22]

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Conclusion