Evolutionary approaches to prolong progression-free survival in breast cancer

A partir d'un modèle numérique évolutionniste paramétré par des expériences in vitro, cette étude évalue l'intérêt d'une stratégie thérapeutique adaptative basée sur des faibles doses de chimiothérapie pour minimiser l'apparition de clones résistants et augmenter la survie sans progression d'un cancer du sein

Résumé en anglais

Many cancers adapt to chemotherapeutic agents by upregulating membrane efflux pumps that export drugs from the cytoplasm, but this response comes at an energetic cost. In breast cancer patients, expression of these pumps is low in tumors before therapy but increases after treatment. While the evolution of therapeutic resistance is virtually inevitable, proliferation of resistant clones is not, suggesting strategies of adaptive therapy. Chemoresistant cells must consume excess resources to maintain resistance mechanisms, so adaptive therapy strategies explicitly aim to maintain a stable population of therapy-sensitive cells to suppress growth of resistant phenotypes through intratumoral competition. We employed computational models parameterized by in vitro experiments to illustrate the efficacy of such approaches. Here we show that low doses of verapamil and 2-deoxyglucose, to accentuate the cost of resistance and to decrease energy production, respectively, could suppress the proliferation of drug-resistant clones in vivo. Compared to compared to standard high dose density treatment, the novel treatment we developed achieved a 2- to 10-fold increase in time to progression in tumor models. Our findings challenge the existing flawed paradigm of maximum dose treatment, a strategy that inevitably produces drug resistance which can be avoided by the adaptive therapy strategies we describe.