The role of cancer in cardiovascular disease

PROJECT SUMMARY/ABSTRACT Cancer and cardiovascular disease remain the world’s two leading killers. Historically considered distinct entities, emerging data have identified numerous shared risk factors, and demonstrated that cancer patients are at increased risk for cardiovascular events. However, these studies have several limitations. For example, most of this work was unable to control for confounding related to traditional risk factors (such as smoking) and cardiotoxic treatments (such as chemotherapy and radiation). Also, causal relationships have not been proven, and potential mechanistic links between the diseases remain obscure. As a result, it is unknown if cancer directly promotes cardiovascular disease, nor whether there are therapies that could potentially treat patients with co-prevalent disease. Given these critical barriers, the broad, long-term goal of this proposal is to precisely determine if cancer promotes cardiovascular disease, and how it can be treated. To answer these questions, we have assembled a diverse team of interdisciplinary investigators who are committed to rigorous and reproducible research across the fields of population genetics, cardio-oncology, and translational medicine. We have established an innovative program that is broad and ambitious, but has been extensively de-risked via our access to unique transgenic animals, highly specialized human biorepositories, and emerging machine learning-based computational methods. Specifically, we now propose three broad lines of investigation. First, we will combine traditional epidemiology and genetic inference approaches to carefully map causal associations and overlapping genetic architecture between cancer and cardiovascular disease. Second, we will use advanced murine lineage- tracing models to prove that cancer can directly promote atherogenesis (independent of shared risk factors), while identifying underlying molecular mechanisms. Third, we will establish a novel drug discovery pipeline, based on artificial intelligence and validated drug repurposing algorithms, which will prioritize translational targets for the larger HLBS community to pursue. If successful, these efforts could transform the field of cardio-oncology while supporting the stated mission of the National Institutes of Health, providing tools for the scientific community, training the next generation of investigators, and leading to the development of new therapies for patients with cancer and cardiovascular disease.