Clinical trial designs for evaluating and exploiting cancer evolution.

The evolution of drug-resistant cell subpopulations causes cancer treatment failure. Current preclinical evidence shows that it is possible to model herding of clonal evolution and collateral sensitivity where an initial treatment could favourably influence the response to a subsequent one. Novel therapy strategies exploiting this understanding are being considered, and clinical trial designs for steering cancer evolution are needed. Furthermore, preclinical evidence suggests that different subsets of drug-sensitive and resistant clones could compete between themselves for nutrients/blood supply, and clones that populate a tumour do so at the expense of other clones. Treatment paradigms based on this clinical application of exploiting cell-cell competition include intermittent dosing regimens or cycling different treatments before progression. This will require clinical trial designs different from the conventional practice of evaluating responses to individual therapy regimens. Next-generation sequencing to assess clonal dynamics longitudinally will improve current radiological assessment of clinical response/resistance and be incorporated into trials exploiting evolution. Furthermore, if understood, clonal evolution can be used to therapeutic advantage, improving patient outcomes based on a new generation of clinical trials.

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