Identification of new combinatory strategies for improving radiotherapy without increasing cardiovascular side effects

Coordinators: J.L. Perfettini (Partner 8) and C. Brenner-Jan (Partner 2)
Starting date: January 2015

Radiation therapy is a cornerstone of cancer management. Most patients saved from cancer are cured by a local regional treatment, in which radiotherapy plays a prominent role. Despite the fact that radiotherapy is one of the most effective forms of cancer treatment, one third of the patients who died from cancer died of a loco-regional failure, underlining the absolute need to optimize the antitumor efficacy of radiotherapy. Considering thattreatment-related comorbidities are major issues for irradiated long-term cancer survivors,the decrease of treatment-associated side effects (such as cardiovascular diseases) is needed for patients who are cured by radiotherapy. The identification of new combinatory strategies that could enhance the antitumor effect of the irradiation, without increasing the treatment-related toxicity is essential for radiotherapy. Recently, we revealed that ionizing radiation triggers the cannibalism of cancer cells and demonstrated that engulfed cells succumb to a novel cell death modality called “entosis”. We also observed that these cellular processes occur when other cell death modalities have been impaired or inhibited. We aim at selectively enhancing “desirable” cell death modality (such as entosis) of the cancer cells, while impairing the “avoidable” cell death of normal cells such cardiac cells (at the origin of radiotherapy-associated cardiovascular diseases) that could succumb to the treatment-associated stress.In this context, the objectives of the iCROC project aim at (i) increasing the knowledge about cell death modalities triggered by ionizing radiation in tumor cells and in stressed cardiomyocytes, (ii) identifying new drugs that could modulate entosis and could be combined with radiotherapy (or other chemotherapies) for the improvement of antitumor treatments, (iii) discovering novel cardioprotective drugs that could prevent the death of cardiomyocytes and could finally help for the identification of new prognosis marker(s) of radio- and chemotherapy efficiency.