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.
EXPECTED RESULTS.
Cardiac stromal cells (CSCs) from irradiated rat hearts display an early pro-fibrotic transcriptomic, phenotypic, and paracrine shift, independent of detectable functional alterations in the heart. Restoration of a beneficial phenotype by activation of autophagy will recover, at least in part, a cardioprotective phenotype of stromal cells, associated to beneficial paracrine and autophagy signaling in the hearts of irradiated rats.
SCIENTIFIC AND TRANSLATIONAL IMPACT.
Late onset cardiac complications can significantly affect quality of life of breast cancer (BC) survivors, and contribute to increased long-term mortality. The incidence of BC in Europe is still rising, albeit prognosis has significantly improved over the years thanks to advancements in oncology. Therefore, the prevalence of BC survivors at risk for cardiac diseases is an emerging health issue, as it will gradually increase, opposing the success in BC treatment in terms of overall long-term survival.
The EMERGENT project will rely on the complementary skills and expertise of the project coordinator with that of co-investigators and external collaborators, all involved in cardiac biomedical research at both translational and clinical levels. The project will provide novel insights on the phenotypic shift towards fibrotic features of resident stromal cells during RT protocols, in order to understand early mechanisms of cardiotoxicity and to test novel preventive strategies against it. The expected results of EMERGENT will potentially propose a novel adjuvant therapy for BC-RT patients to prevent early mechanisms of cardiotoxicity before the onset of clinical signs, thus reducing the late incidence of cardiovascular complications, and possibly increasing the overall long-term survival of BC survivors.
The integrated research approach of EMERGENT will complete the proposed aims of understanding the phenotypic shift of CSCs during RT, also discovering novel pathways (for example linked to autophagy modulation or non-coding RNAs) affecting their features and myofibroblast differentiation. This approach, in which biotechnological and medical competences will be synergistically integrated, will promote research excellence, and provide results that, in the near future, could be translated into effective and innovative therapeutic protocols, with successful transfer from scientific knowledge to clinical practice.