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

整合基因组学和蛋白质相互作用组用于 HPV 头颈癌治疗

基本信息

批准号：
10664975
负责人：
Jennifer Rubin Grandis
金额：
$ 94.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664975
关键词：
Address Basic Science Cancer Etiology Clinical Clinical Treatment Clinical Trials Dependence Disease ERBB3 gene Epidemic Epidemiology Epidermal Growth Factor Receptor Family member Genital Genitalia Genomics Growth Head and Neck Cancer Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Incidence Individual Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Maps Mediating Metastatic/Recurrent Molecular Morbidity - disease rate Mutation Operative Surgical Procedures PIK3CA gene PIK3CG gene PTEN gene Pathogenesis Patient Care Patients Positioning Attribute Pre-Clinical Model Proteins Research Role Signal Transduction Smoker Translating Translational Research Vaccination boys cancer therapy chemoradiation experience functional genomics girls head and neck cancer patient innovation multidisciplinary new epidemic new therapeutic target non-smoker novel strategies novel therapeutic intervention oral HPV-positive head and neck cancers predictive marker programs success

项目摘要

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.

项目摘要/摘要两者中，由人乳头瘤病毒（HPV）引起的头颈癌的新兴流行病吸烟者和非吸烟者。虽然生殖器HPV暴露之前男孩和女孩的疫苗接种可能会减少 HPV+ HNC，几十年来将无法实现疫苗接种的影响。同时，HPV+ HNC患者是用毁容的手术和联合化学放疗方法处理，这与重大的短期和长期病毒。通常具有复发/转移性HPV+ HNC的个体屈服于他们的疾病。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，癌症蛋白质之间的物理相互作用网络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，毒性更少疗法。在此提案中，我以我们过去的成功为基础1）定义HNC中的主要基因组“驱动器”变化； 2）开发新颖的治疗方法； 3）使用相关临床前翻译我们的发现模型进入HNC患者的临床治疗。我未来的研究计划寻求1）定义关键与蛋白质相互作用组的结合结合介导HPV+ HNC生长的遗传改变确定新的治疗靶标； 2）确定每个目标的机制及其在HPV+ HNC中的作用；和 3）将这些发现转化为HPV+ HNC的新治疗方法。我将从研究具有的目标开始在我们的研究中出现了与HPV+ HNC相关的研究，例如激活磷脂酰肌醇3-的改变激酶（PI3K）信号传导，包括PIK3CA的突变或扩增，PTEN损失以及激活 EGFR家庭成员Her3。当相关时，我将将这些发现扩展到其他HPV+癌症颈癌和肛门癌以及HPV-HNC，仍然致命。在分子方面具有深厚的专业知识 HNC患者的发病机理和护理；经验领导的多学科团队专注于这种疾病的翻译研究方法以及丰富的基础科学和临床网络合作者，我在此提案中划定的7年研究计划中取得了独特的位置。