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

项目概要/摘要 有一个新的流行病的头部和颈部癌症引起的人乳头瘤病毒（HPV）， 吸烟者和不吸烟者。虽然在生殖器HPV暴露之前接种疫苗的男孩和女孩可能会减少 HPV+ HNC，疫苗接种的影响几十年内都不会实现。HPV+ HNC患者 通过毁容手术和联合放化疗方法治疗，这与 严重的短期和长期发病率。复发性/转移性HPV+ HNC的个体通常 屈服于他们的疾病我的研究计划将应用功能基因组学的新方法， 相关和独特HPV+ HNC中癌蛋白之间物理相互作用的映射网络 临床前模型，将这种恶性肿瘤中的癌症依赖性转化为更有效和毒性更低的 治疗在这个建议中，我建立在我们过去成功的基础上：1）定义HNC中关键的基因组“驱动”改变; 2)开发新的治疗方法;以及3）使用相关的临床前研究成果转化我们的发现 用于HNC患者的临床治疗。我未来的研究计划是：1）定义 介导HPV+ HNC生长的遗传改变以及蛋白质相互作用组的测定 确定新的治疗靶点; 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HPV+ HNC的新治疗方法。我将开始研究目标， 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- 在一些实施方案中，本发明涉及一种用于抑制PI 3 K信号传导的方法，包括PIK 3CA的突变或扩增，或PTEN缺失，以及PIK 3CA的激活。 EGFR家族成员HER 3。当相关时，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。在分子生物学领域有着深厚的专业知识 HNC患者的发病机制和护理;领导多学科团队的经验， 这种疾病的转化研究方法和丰富的基础科学和临床网络 合作者，我独特的定位，成功地在7年的研究计划中描绘了这一建议。

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.