Integrating genomics and the protein interactome for HPV+ head and neck cancer therapy

项目摘要/摘要 由人类乳头瘤病毒(HPV)引起的头颈部癌症在这两个地区都出现了新的流行 吸烟者和不吸烟者。而男孩和女孩在生殖器HPV暴露之前接种疫苗可能会减少 HPV HNC，接种疫苗的影响几十年内不会意识到。与此同时，HPV HNC患者正在 接受毁容手术和联合放化疗治疗，这与 重大的短期和长期疾病。复发/转移性HPV HNC患者一般 屈服于他们的疾病。我的研究计划将在功能基因组学和 在相关和独特的HPV HNC中定位肿瘤蛋白之间的物理相互作用网络 将这种恶性肿瘤的癌症依赖性转化为更有效和毒性更低的临床前模型 治疗。在这项提案中，我将在我们过去成功的基础上，1)定义HNC中关键的基因组“驱动因素”改变； 2)开发新的治疗方法；3)将我们的发现转化为相关的临床前研究 模型转化为HNC患者的临床治疗。我未来的研究计划寻求1)定义关键 调节HPV HNC生长的基因改变与蛋白质相互作用组的测定 寻找新的治疗靶点；2)确定每个靶点的机制及其在HPV HNC中的作用；以及 3)将这些发现转化为治疗HPV HNC的新方法。我将从对目标的研究开始 在我们的研究中出现了与HPV HNC相关的变化，例如激活磷脂酰肌醇3- PI3K信号通路包括PIK3CA的突变或扩增，或PTEN的丢失，以及PIK3CA的激活 EGFR家族成员HER3。如果相关，我将把这些发现扩展到其他HPV癌症，包括 宫颈癌和肛门癌以及HPV-HNC，它们仍然是致命的。在分子方面有深厚的专业知识 HNC患者的发病机制和护理；领导多学科团队专注于 这种疾病的翻译研究方法和丰富的基础科学和临床网络 合作者们，我有得天独厚的优势，能够成功地完成这项提案中所描绘的7年研究计划。

Project Summary/Abstract There is an emerging epidemic of head and neck cancer caused by human papillomavirus (HPV) among both smokers and nonsmokers. While vaccination of boys and girls prior to genital HPV exposure is likely to reduce HPV+ HNC, the impact of vaccination won’t be realized for decades. In the meantime, HPV+ HNC patients are treated with disfiguring surgeries and combined chemoradiation approaches, which are associated with significant short- and long-term morbidities. Individuals with recurrent/metastatic HPV+ HNC generally succumb to their disease. My research program will apply new approaches in functional genomics and mapping networks of physical interactions among cancer proteins in relevant and unique HPV+ HNC preclinical models to translate cancer dependencies in this malignancy into more effective and less toxic therapies. In this proposal, I build upon our past success in 1) defining key genomic “driver” alterations in HNC; 2) developing novel therapeutic approaches; and 3) translating our discoveries using relevant preclinical models into clinical treatments for HNC patients. My future research program seeks to 1) define the key genetic alterations that mediate HPV+ HNC growth in conjunction with determination of the protein interactome to identify new therapeutic targets; 2) determine the mechanisms of each target and its role in HPV+ HNC; and 3) translate these findings into new treatments for HPV+ HNC. I will begin with the study of targets that have emerged in our research as relevant in HPV+ HNC such as alterations that activate phosphatidylinositol 3- kinase (PI3K) signaling including mutation or amplification of PIK3CA, or PTEN loss, and activation of the EGFR family member HER3. When relevant, I will extend these findings to other HPV+ cancers including cervical and anal cancers as well as HPV- HNC, which remain lethal. With deep expertise in the molecular pathogenesis and care of patients with HNC; experience leading multi-disciplinary teams focused on translational research approaches for this disease and a rich network of basic science and clinical collaborators, I am uniquely positioned to succeed in the 7 year research plan delineated in this proposal.