Grant: Project Grant

Background: A staggering 42% of childhood cancer patients develop disabling/life-threatening adverse drug reactions (ADRs). Anthracyclines are widely used for the treatment of ~70% of adult and childhood cancers. However, anthracyclines cause serious heart damage in 5-16% of patients, resulting in death or life-long disability. Currently prevention is limited to reducing the dose of anthracyclines or using a second drug to protect the heart, dexrazoxane. However, dose reduction reduces anti-cancer effectiveness and dexrazoxane is restricted to adult patients with advanced cancer receiving high anthracycline doses, and dexrazoxane is not approved for use in pediatric patients due to risks of secondary cancers. Our goal is to prevent anthracycline-cardiotoxicity. We identified that the RARG gene is related to anthracycline-cardiotoxicity in a large children's cancer study (Nat Gen, 2015). Building upon these findings, we will pursue two prevention strategies: 1. Develop a novel cardioprotectant that disrupts the RARG pathway. We will screen a panel of targeted drugs in a human cardiac cells, followed by evaluation in well-established animal models of anthracycline-cardiotoxicity. We have now demonstrated proof-of-principle for 2 drugs exhibiting up to 95% cardioprotection in cultured cardiac cells and these were more effective than dexrazoxane. 2. Identify new genetic risk factors to pre-emptively identify patients at higher risk of anthracycline-cardiotoxicity. We have collected DNA from a large group of adult patients for high-throughput genomic analyses. We will combine pediatric and adult studies to improve the study. Validated factors will be incorporated into a predictive test and explored as additional candidates for strategy #1. Expected Outcomes: A new safe and effective anthracycline-cardioprotectant will be primed for clinical evaluation in patients. New genetic risk factors will be transitioned to a clinical testing program.