T1-3

Prevent adverse cardiotoxicity induced by anti-cancer therapy

Coordinators: M.C. Vozenin (Partner 8) and E. Morel (Partner 2)
Financial support from January 2012 until December 2014

Cardiotoxicity is among the chronic toxicities that alter quality of life and survival of patients under anti-cancer treatment. HF is a significant delayed side effect of both chemo- and radiotherapy and will become a major concern within the next years. The most adverse cardiac events are those related to radiotherapy, anthracyclines and their combination specially in pediatric patients, and in patients treated with targeted therapies including herceptin associated or not with radiation therapy. Despite the increasing occurrence of these chronic toxicities, this field of research remains underserved. Partner 8 is one of the rare French laboratories studying the biological basis of the radiotherapy and its consequences on tumors and normal tissues. A proof of concept has emerged recently linking anti-cancer treatments-induced cardiac toxicity and small G proteins. As shown above, Partner 2 has emphasized the role of Epac1 and the small G protein signaling cascade in the context of maladaptive cardiac hypertrophy and HF. Of interest, Epac1 activates common targets of the doxorubicin-induced pathway such as the small G protein Rac and mTOR.
Deliverables:
1. Identification of predictive biomarkers of cardiac disease from blood samples collected in breast and pediatric patients. Genetic polymorphism at the whole genome level (SNPs) will be performed as data reported in breast cancer patients support the relevance of SNPs to predict individual radiation sensitivity and show that possession of multiple SNPs associated with radiosensitivity correlates with an increased probability for developing severe radiation-induced sequels39.
2. Investigation of the alteration of cardiac physiological parameters using appropriate imaging on a cohort of 101 patients treated by radiotherapy for breast cancer. Preliminary results show early presence of cardiac hypertrophy without occurrence of any cardiac symptomatology reported so far, suggesting that radiation-induced cardiac remodeling is a progressive process initiated far before occurrence of any symptoms. Combined with predictive markers and imaging, this opens a new early therapeutic window and would help to improve long term follow up of patients.
3. The aim is to understanding the molecular and physiopathological basis of the radio- and anthracyclines- induced cardiac signaling response leading to the classical pattern of hypertrophy and heart failure and specially the small G-proteins.
4. Patenting and valorization will be undertaken at each step when applicable with the appropriate partners.