Cancer Treatment As Pest Management: Exploiting Evolutionary Dynamics to Optimize Therapy

A number of successful systemic therapies are available for treatment of disseminated cancers. However, tumor response to these treatments is almost invariably transient and therapy fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations.  Interestingly, although cancers are highly dynamic systems, cancer therapy is typically administered according to a fixed, linear protocol.  Treatment is changed only when the tumor progresses but successful tumor adaptation begins immediately upon administration of the first dose.  Applying evolutionary models to cancer therapy demonstrate the potential advantage of using more dynamic, strategic approaches that focus not just on the initial cytotoxic effects of treatment but also on the evolved mechanisms of cancer cell resistance and the associated phenotypic costs.  The goal of evolutionary therapy is to prevent or exploit emergence of adaptive tumor strategies. Examples of this approach include adaptive therapy and double bind therapy. The former continuously alters therapy to maintain a stable tumor volume using a persistent population of therapy-sensitive cells to suppress proliferation of resistant phenotypes. The latter uses the cytotoxic effects of an initial therapy to promote phenotypic adaptations that are then exploited using follow-on treatment.  In pre-clinical models, application of adaptive therapy permits indefinite tumor control with a single cytotoxic drug.  Clinical results from studies using adaptive therapy and double bind therapy will be presented.