An individualized network medicine infrastructure for precision cardio-oncology

癌症治疗对心功能不全的认识日益提高，导致了新兴的心功能领域， 肿瘤学然而，在如何预防和治疗新的心脏毒性方面没有指导方针， 癌症幸存者由于有限的实验测定。网络医学-一门旨在重新定义 疾病和治疗从综合的角度使用系统生物学和网络科学-提供了一个 非侵入性的方式来识别心脏肿瘤学的可行生物标志物。这五年的职业发展 该计划将开发最先进的系统药理学和网络医学方法，在心脏， 肿瘤学，重点是筛查，监测和治疗患有心功能不全的癌症幸存者 为了促进主要研究者（PI）Feixiong博士的职业目标， 程有了这个应用程序，PI将坚持在东北严格的指导培训课程 丹娜-法伯癌症研究所和哈佛的布里格姆妇女医院（BWH）。PI的 导师Albert-Laszlo Barabasi博士是网络科学领域的世界领先专家之一， 与他的共同导师约瑟夫Loscalzo博士和塞巴斯蒂安Schneeweiss，在BWH强大的合作关系。 博士Loscalzo，一位有影响力的心脏病专家，将为PI提供心血管生物学培训，职业指导， 并就拟议研究计划的执行提供科学建议。施尼维斯博士， 药物流行病学家，将为PI提供关于应用计算密集型算法的培训， 分析患者纵向大数据。该方案提出了两个具体目标：（1）发展一个国家， 最先进的系统药理学方法，即全基因组定位系统药物网络（GPSDnet） 算法，以阐明心脏毒性的景观，以各种癌症药物（K99）-中央，统一 GPSDnet的假设是，一种集成的、基于机制的网络方法， 代测序数据，药物靶点网络，药物诱导的转录组，人类相互作用组，沿着 根据FDA不良事件报告系统的不良事件报告和患者纵向数据， 证明了一种用于评价当前癌症治疗的心脏毒性的新的和有效的方法（例如，多靶 激酶抑制剂）和新疗法（例如，免疫检查点抑制剂）; 2）肿瘤学干扰， 诊断、预防和病人护理（R 00）-目标2将强调网络医学的使用 鉴定可操作的生物标志物的技术（例如，由癌细胞共享的共形网络模块， 心血管细胞/系统）用于推进心脏肿瘤学异质性的表征，从而 实现以患者为中心的协调治疗和长期心血管护理策略的目标 (e.g.,心脏衰竭和冠状动脉疾病）。总而言之，批准K99奖 将是宝贵的，在建立博士郑作为一个独立的研究者，利用承诺， 精准医疗需要专门从事网络医学的专家。

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 this K99 award will be invaluable in establishing Dr. Cheng as an independent investigator by exploiting the promise of precision medicine that is in need of experts specializing in network medicine for cardio-oncology.