An individualized network medicine infrastructure for precision cardio-oncology

人们对癌症治疗引起的心脏功能障碍的认识日益增强，这导致了心血管领域的新兴领域。 肿瘤学。然而，对于如何预防和治疗这种新的心脏毒性，目前还没有指导方针。 由于有限的实验分析，癌症幸存者。网络医学--一门试图重新定义 使用系统生物学和网络科学的综合视角的疾病和治疗学-提供 非侵入性识别心脏肿瘤学可操作生物标志物的方法。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- 专注于筛查、监测和治疗患有心脏功能障碍的癌症幸存者的肿瘤学 来自癌症治疗的促进职业目标的结果给首席研究员(PI)，飞雄博士 程先生。通过这项申请，PI将在东北地区坚持严格的导师培训课程 达纳-法伯癌症研究所和哈佛大学布里格姆妇女医院(BWH)。少年派的 导师阿尔伯特-拉兹洛·巴拉巴西博士是网络科学领域的世界领先专家之一，他已经 与他的共同导师约瑟夫·洛斯卡尔佐博士和塞巴斯蒂安·施尼韦斯博士在BWH建立了密切的合作关系。 洛斯卡尔佐博士是一位有影响力的心脏病专家，他将为PI提供心血管生物学培训、职业指导、 以及关于执行拟议研究计划的科学建议。施尼韦斯博士，总理 药物流行病学家，将为PI提供应用计算密集型算法的培训 分析患者纵向大数据。该计划提出了两个具体目标：1)发展国家-- ART系统药理学方法，即全基因组定位系统药物网络(GPSDnet) 算法，以阐明各种抗癌药物(K99)的心脏毒性图景-中央，统一 GPSDnet的假设是，一种集成的、基于机制的网络方法，它结合了NEXT- 世代测序数据，药物靶标网络，药物诱导转录组，人类交互作用组，以及 根据FDA的不良事件报告系统和患者的纵向数据，Will 证明了一种新的和有效的方法来评估当前癌症治疗的心脏毒性(例如，多靶点 激酶抑制剂)和新疗法(例如，免疫检查点抑制剂)；2)心脏肿瘤学扰动， 诊断、预防和患者护理(R00)-目标2将强调网络医学的使用 识别可操作的生物标记物的技术(例如，由癌细胞和 心血管细胞/系统)，以促进心脏肿瘤异质性的表征，从而 实现协调、以患者为中心的治疗和长期心血管护理战略的目标 (例如，心力衰竭和冠状动脉疾病)给癌症幸存者。总而言之，K99奖的批准 将通过利用以下承诺使郑博士成为一名独立的调查员 需要心脏肿瘤学网络医学专家的精准医学。

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.