Most breast cancer (BC) patients undergo radiotherapy (RT) as part of their treatment. Left BC-RT inevitably leads to coincidental irradiation of the heart, resulting in a bystander cardiotoxic effect. In fact, these patients face an increased long-term risk of several kinds of heart diseases, including ischemic heart disease and congestive heart failure. The mechanisms involved in cardiotoxicity at therapeutic radiation doses, though, are still largely unknown. Evidence indicates a role for radiation-induced vascular injury, leading to inflammatory and thrombotic events, focal ischemia, and interstitial fibrosis. The involvement of cardiac stromal cells (CSCs) in these pathogenetic events is still to be elucidated.
The present project proposal is based on the hypothesis that fibrotic polarization of CSCs mediates early mechanisms of cardiotoxicity, and that retrieval of a beneficial phenotype may be protective against cardiac side effects of RT. EMERGENT will exploit a clinically relevant model of chest irradiation in adult female rats, with highly optimized heart dosimetry, with late onset cardiac dysfunction. EMERGENT aims at: 1) elucidating the features of CSC functional phenotype and pro-fibrotic polarization from early stages of RT cardiotoxicity before impairment of cardiac function, and 2) establishing a proof-of-concept adjuvant therapy during RT mediated by an anti-fibrotic effect on CSCs. The expected results of EMERGENT will provide a novel protective strategy for BC-RT patients to prevent cardiotoxicity, thus possibly reducing the late incidence of cardiovascular complications and increasing the overall long-term survival of BC survivors.