CYP1 Inhibition as a New Therapeutic Strategy for Doxorubicin Cardiomyopathy

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PROJECT SUMMARY This proposal reflects a five-year career development plan for Dr. Aarti Asnani, a staff cardiologist at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor at Harvard Medical School (HMS). Dr. Asnani’s research focuses on anthracycline-induced cardiomyopathy, a major contributor to morbidity and mortality in the growing population of cancer survivors. Based on her chemistry background and clinical expertise in cardio-oncology, Dr. Asnani is uniquely well-positioned to characterize the biochemical pathways that contribute to chemotherapy-induced cardiotoxicity in order to identify new cardioprotective therapies. In 2017, Dr. Asnani was recruited to BIDMC where she serves as Associate Director of the Cardio-Oncology Program. Dr. Robert Gerszten, Chief of Cardiovascular Medicine at BIDMC, has been very involved in Dr. Asnani’s career development since 2006 and will serve as the primary on-site mentor for this project. Dr. Gerszten has expertise in the use of metabolite profiling and proteomics to identify new pathways that contribute to cardiometabolic disease. Dr. Asnani will also continue to receive mentorship from her postdoctoral advisor, Dr. Peterson, whose laboratory moved to the University of Utah in January 2017. Dr. Peterson is an expert in chemical biology and has pioneered the use of zebrafish for drug discovery and mutagenesis. Both preceptors are well-funded and have a longstanding history of mentoring successful junior faculty. In addition to this combined training approach, Dr. Asnani’s Scientific Advisory Committee consists of world-class scientists (Drs. MacRae, Liao, Pandolfi, and Nebert) who will contribute expertise in animal models of cardiomyopathy, cancer cell biology, and pharmacology. Dr. Asnani benefits from strong institutional support and a rich research environment. She has access to a broad range of core facilities and equipment, scientific expertise, and opportunities for collaboration that extend across BIDMC, Longwood Medical Area, and HMS. In this application, Dr. Asnani has outlined a series of experiments to elucidate the role of Cytochrome P450 family 1 (CYP1) enzymes as new therapeutic targets for doxorubicin cardiotoxicity. Prior work in Dr. Peterson’s lab identified the small molecule visnagin, a CYP1 inhibitor, as protecting against doxorubicin-induced cardiomyopathy in zebrafish and mice. In this proposal, Dr. Asnani will use transgenic zebrafish models to identify the specific CYP1 isoform responsible for cardiotoxicity. She will use Cyp1a1/1a2/1b1(−/−) knockout mice to establish whether genetic inhibition of CYP1 enzymes protects against doxorubicin cardiotoxicity in a mammalian model. Finally, she will use a mouse xenograft model to determine the effect of CYP1 inhibition on doxorubicin’s anti-tumor activity. By completing the proposed project, Dr. Asnani will complement her prior training in metabolite profiling, chemical biology, and zebrafish models with additional training in transgenic techniques and mouse models. These experiments will form the basis for an independent investigative platform that will seek to develop new treatments for patients with chemotherapy-induced cardiotoxicity.