The proposed program aims to evaluate the efficacy of molecules enhancing the effects of radiotherapy, in in vitro and in vivo models of breast cancer. Two types of molecules, namely an inhibitor of mitochondrial genome maintenance and an inhibitor of the Base Excision Repair pathway, will be tested for radiopotentiation efficacy in the models.
The proposed inhibitors, whether targeting mitochondrial genome maintenance or the BER pathway, are already being investigated in vitro, both in the laboratory and by collaborators. We have shown that inhibition of the mechanisms targeted leads to an impairment in DNA damage repair following genotoxic stress. During this project, we will evaluate the effects of inhibitors on DNA damage repair induced by irradiation of different types (conventional, ultra-high dose rate, even extreme dose rate) and the associated mechanisms.
Variability in response to therapeutic combinations is frequently observed when moving from in vitro to in vivo models. We will therefore evaluate the inhibitors on cell line models well characterized in the laboratory, and corresponding to different breast cancer subtypes. On the other hand, the studies will be completed by a validation of the effects observed in vitro on a murine model of breast cancer. This xenograft model, developed in immunocompetent animals, will enable us to monitor the clinical, histological and immune response of the animals and their tumors, in order to confirm the interest of the molecules for therapeutic application in support of radiotherapy.
The proposed program will benefit from the laboratory's collaborations with physicists and chemists, and IRCM's experimental facilities and platforms (irradiation, animal experimentation, microscopy, cytometry, etc.).