The growing awareness of cardiac dysfunction by cancer treatment has led to the emerging field of cardio- oncology. However, there are no guidelines in terms of how to prevent and treat the new cardiotoxicity in cancer survivors due to the limited experimental assays. Network medicine – a discipline that seeks to redefine disease and therapeutics from an integrated perspective using systems biology and network science – offers a non-invasive way to identify actionable biomarkers for cardio-oncology. This five-year career development program will develop state-of-the-art systems pharmacology and network medicine approaches in cardio- oncology that focuses on screening, monitoring, and treating cancer survivors with cardiac dysfunction resulting from cancer treatment for facilitating the career goals to the principal investigator (PI), Dr. Feixiong Cheng. With this application, the PI will adhere to a rigorous mentored training curriculum in Northeastern University, Dana-Farber Cancer Institute, and Harvard’s Brigham and Women's Hospital (BWH). The PI’s mentor, Dr. Albert-Laszlo Barabasi, one of the world’s leading experts in the field of network science, has strong collaborative relations with his co-mentors, Drs. Joseph Loscalzo and Sebastian Schneeweiss, in BWH. Dr. Loscalzo, an influential cardiologist, will provide the PI with cardiovascular biology training, career guidance, and scientific advice on the execution of the proposed research plan. Dr. Schneeweiss, a premier pharmacoepidemiologist, will provide the PI with training on applying computationally intensive algorithms for analyzing patient longitudinal big data. This program proposes two specific aims: 1) Development of a state-of- the-art systems pharmacology approach, namely genome-wide positioning systems drug network (GPSDnet) algorithm, to illuminate the landscape of cardiotoxicity to various cancer agents (K99) - The central, unifying hypothesis of GPSDnet is that an integrated, mechanism-based, network approach which incorporates next- generation sequencing data, drug-target networks, drug-induced transcriptome, the human interactome, along with adverse event reports from the FDA’s Adverse Event Reporting System and patient longitudinal data, will prove a novel and effective way for evaluation of cardiotoxicity for current cancer therapies (e.g., multitargeted kinase inhibitors) and new therapies (e.g., immune checkpoint inhibitors); 2) Cardio-oncology perturbation, diagnosis, prevention, and patient care (R00) - The Aim 2 will emphasize the use of network medicine techniques to identify actionable biomarkers (e.g., comorbidity network modules shared by cancer cells and cardiovascular cells/systems) for advancing the characterization of cardio-oncology heterogeneity, thereby achieving the goal of coordinated, patient-centered strategies for treatment and long-term cardiovascular care (e.g., heart failure and coronary artery disease) for cancer survivors. In summary, approval of ...