A Multi-omics evaluation of Carfilzomib-related Cardiotoxicity

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Cardiotoxicity related to cancer therapies is such a significant clinical problem that NCI and NHLBI have jointly issued PA-19-112 to stimulate applications with the intent to mitigate cardiovascular dysfunction while optimizing cancer outcomes. Cardiotoxicity, such as heart failure (HF), related to the proteasome inhibitor carfilzomib has been an increasingly recognized adverse event that contributes to the symptom burden and poor outcomes of multiple myeloma (MM) patients. Given the knowledge gap in the understanding of carfilzomib-related cardiotoxicity, a pharmacogenomic approach may identify pharmacogenomic/metabolomic biomarkers of such adverse effect and provide an opportunity to improve cardiovascular outcome of cancer patients in a personalized manner. Our long-term goal is to identify and institute preventive strategies for cancer patients at high risk for carfilzomib-related cardiotoxicity, prior to administration of this cardiotoxic treatment, in order to prevent or minimize such risk. Our central hypothesis is that characteristic biomarkers for carfilzomib-related cardiotoxicity can be discerned through interrogation of multi-omics data. Our preliminary results demonstrate the feasibility of such an approach and suggest that the metabolomic and proteomic profiles of carfilzomib-related HF are similar to those of HF in non-cancer patients. More importantly, our findings support the hypothesis that there are overlapping pathways in the development of cardiotoxicity induced by carfilzomib and anthracyclines. The overall objectives of this application are to identify and validate metabolomic and pharmacogenomic biomarkers for carfilzomib-related HF in MM patients using a multi-omics approach and existing whole exome sequencing (WES) data from the Oncology Research Information Exchange Network (ORIEN), and in large electronic health record (EHR) systems, namely the UK Biobank and biobank at Vanderbilt University (BioVU). We have assembled a multidisciplinary team to carry out the following three specific aims: 1). Identify and validate metabolomic biomarkers at baseline that differentiate MM patients who develop versus do not develop carfilzomib-related HF. 2). Identify and replicate germline genetic variants associated with carfilzomib-related HF among MM patients. 3). Build and validate a predictive model for carfilzomib-related HF among MM patients. The proposed work is expected to provide tools to enable stratification of MM patients for cardiotoxicity risk based on pharmacogenomic and metabolomic biomarkers and provide the basis for clinical translation of these biomarkers. In addition, this work will also provide important insight as to what extent the genetic variants associated with anthracycline-related cardiotoxicities are also associated with carfilzomib-related HF. Ultimately, our research will potentially lead to a paradigm shift in current clinical practice to better prevent cardiotoxicity, and improve outcomes in the MM patient population.