Individualized medicine to predict and prevent chemotherapy-related heart failure

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). 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 at TRPC6 and other known and novel loci, significantly increase patient risk of cardiotoxicity. Determination of these variants and better understanding of their mechanisms of action will allow individualized risk stratification and mitigation of chronic heart failure. To determine genetic risk variants of dox-related cardiotoxicity and new cardioprotective strategies for at-risk patients, we will: 1. Diversify our existing cardiotoxicity biorepository at Mayo Clinic Florida by extending to Mayo Clinic Arizona, The University of Florida Jacksonville and Moffitt Cancer Center, performing exome sequencing of these newly enrolled patients and meta-analyses of top hits with additional large and diverse datasets. 2. Define the mechanistic basis of TRPC6 gain-of-function and interaction with other doxorubicin-induced toxicity pathways. 3. Assess the efficacy and cardioprotection of TRPC6 inhibitors in a tumorigenic mouse model analogous to triple negative breast cancer.