Application of Evolutionary Principles to Cancer Therapy

Abstract

The dynamic cancer ecosystem, with its rich temporal and spatial diversity in environmental conditions and heritable cell phenotypes, is remarkably robust to therapeutic perturbations. Even when response to therapy is clinically complete, adaptive tumor strategies almost inevitably emerge and the tumor returns. Although evolution of resistance remains the proximate cause of death in most cancer patients, a recent analysis found that evolutionary terms were included in less than 1% of articles on the cancer treatment outcomes, and this has not changed in 30 years. Here, we review treatment methods that attempt to understand and exploit intratumoral evolution to prolong response to therapy. In general, we find that treating metastatic (i.e., noncurable) cancers using the traditional strategy aimed at killing the maximum number of tumor cells is evolutionarily unsound because, by eliminating all treatment-sensitive cells, it enables rapid proliferation of resistant populations-a well-known evolutionary phenomenon termed "competitive release." Alternative strategies, such as adaptive therapy, "ersatzdroges," and double-bind treatments, shift focus from eliminating tumor cells to evolution-based methods that suppress growth of resistant populations to maintain long-term control.

Fig. 1. Examples of evolutionary cancer treatment strategies

Panel A demonstrates therapy for a mixed population of sensitive and resistant cells. Adaptive therapy reduces the tumor population but explicitly maintains a small population of treatment-sensitive cells. Once an initial tumor response is achieved, therapy is discontinued. In the absence of treatment, sensitive cells have a fitness advantage and will proliferate at the expense of the resistant cells. While the resistant cells will eventually dominate, the goal is to maintain tumor control with therapy for the longest possible time period. Panel B illustrates a double bind approach in which the resistance mechanism to one therapy can be treated with the other therapy (see text for example). Combining the two therapies will simply select for an alternative adaptive pathway and only slightly delays time to progression (not shown). However, by administering them in sequence, the evolutionary dynamics (termed “predator facilitation”) forces the cancer cells to oscillate between phenotypes. This is an evolutionarily futile cycle which can permit long term control of an invasive species.