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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：
9982266
负责人：
Jennifer Rubin Grandis
金额：
$ 77万
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/9982266
关键词：
1-Phosphatidylinositol 3-Kinase Address Basic Science Cancer Etiology Clinical Clinical Treatment Clinical Trials Dependence Disease ERBB3 gene Epidemic Epidemiology Epidermal Growth Factor Receptor Family member Genital system Genomics Growth Head and Neck Cancer Human Papillomavirus Incidence Individual Malignant Neoplasms Mediating Metastatic/Recurrent Molecular Morbidity - disease rate Mutation Operative Surgical Procedures PIK3CA 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 cervical and anal cancer chemoradiation experience functional genomics girls head and neck cancer patient human interactome innovation multidisciplinary new therapeutic target non-smoker novel strategies novel therapeutic intervention 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.

项目总结/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。我未来的研究计划旨在1）定义关键介导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的新疗法。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。