A theoretical quantitative model for evolution of cancer chemotherapy resistance

Disseminated cancer remains a nearly uniformly fatal disease. While a number of effective chemotherapies are available, tumors inevitably evolve resistance to these drugs ultimately resulting in treatment failure and cancer progression. Causes for chemotherapy failure in cancer treatment reside in multiple levels: poor vascularization, hypoxia, intratumoral high interstitial fluid pressure, and phenotypic resistance to drug-induced toxicity through upregulated xenobiotic metabolism or DNA repair mechanisms and silencing of apoptotic pathways. We propose that in order to understand the evolutionary dynamics that allow tumors to develop chemoresistance, a comprehensive quantitative model must be used to describe the interactions of cell resistance mechanisms and tumor microenvironment during chemotherapy.Ultimately, the purpose of this model is to identify the best strategies to treat different types of tumor (tumor microenvironment, genetic/phenotypic tumor heterogeneity, tumor growth rate, etc.). We predict that the most promising strategies are those that are both cytotoxic and apply a selective pressure for a phenotype that is less fit than that of the original cancer population. This strategy, known as double bind, is different from the selection process imposed by standard chemotherapy, which tends to produce a resistant population that simply upregulates xenobiotic metabolism. In order to achieve this goal we propose to simulate different tumor progression and therapy strategies (chemotherapy and glucose restriction) targeting stabilization of tumor size and minimization of chemoresistance.

This work confirms the prediction of previous mathematical models and simulations that suggested that administration of chemotherapy with the goal of tumor stabilization instead of eradication would yield better results (longer subject survival) than the use of maximum tolerated doses. Our simulations also indicate that the simultaneous administration of chemotherapy and 2-deoxy-glucose does not optimize treatment outcome because when simultaneously administered these drugs are antagonists. The best results were obtained when 2-deoxy-glucose was followed by chemotherapy in two separate doses.

These results suggest that the maximum potential of a combined therapy may depend on how each of the drugs modifies the evolutionary landscape and that a rational use of these properties may prevent or at least delay relapse.

This article was reviewed by Dr Marek Kimmel and Dr Mark Little.