PROJECT SUMMARY/ABSTRACT Chemotherapy-related cardiotoxicity leading to heart failure is a major issue in the treatment of breast cancer and lymphoma patients, who are three times more likely to get heart failure than controls. Cumulative dose of the anthracycline chemotherapy, doxorubicin, is strongly associated with increased risk of heart failure, such that patients are limited to a lifetime cumulative dose, even if the therapy is still needed. Doxorubicin is commonly used for treatment of lymphoma and high risk breast cancers, (triple negative and HER2+ breast cancer). For HER2+ patients, doxorubicin is used in combination with the HER2 targeted therapy, trastuzumab which also increases the risk of cardiotoxicity. Unfortunately, prediction of which cancer patients are at risk of heart failure is poor and current cardioprotective therapies are limited. Our published genetic studies have identified TRPC6 as a risk locus for doxorubicin-induced heart failure. Our studies of ipsc-derived cardiomyocytes and a mouse model of doxorubicin-induced cardiomyopathy showed that therapeutic inhibition of TRPC6 and TRPC6 knock-out are protective against doxorubicin-induced cardiotoxicity. Our preliminary studies and those of others suggest that inhibition of TRPC6 may also have anti-tumor properties. The overall scientific premise of this project is that genetic variants that increase TRPC6 expression or result in gain-of- function are associated with doxorubicin-related heart failure, and that characterization of TRPC6 inhibitors will improve the care of patients requiring chemotherapy. To further characterize the role of TRPC6 in doxorubicin- related heart failure, and to test the efficacy of TRPC6 inhibition in combination with doxorubicin treatment, we will: 1. Test for genetic association of TRPC6 and other known risk genes in multiple, large well characterized samples of lymphoma and breast cancer patients. 2. Determine in vitro which variants result in gain-of-function and which inhibitors prevent the gain-of-function. 3. Assess the efficacy and cardioprotection of TRPC6 inhibitors in a tumorigenic mouse model analogous to triple negative breast cancer.

PROJECT NARRATIVE Cancer patients treated with the common chemotherapy drug doxorubicin are at increased risk of heart failure. This project will characterize genetic markers to identify which patients are at risk of chemotherapy-related heart failure and evaluate an experimental treatment to prevent heart failure.