Molecular Mechanisms of Tumor Behavior and Response to Therapy in HPV-positive Oropharyngeal Cancer

HPV 阳性口咽癌肿瘤行为和治疗反应的分子机制

基本信息

批准号：
10247104
负责人：
THOMAS E. CAREY
金额：
$ 5.27万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247104
关键词：
Advocate Affect Aftercare Alcohols Alternative Therapies Behavior Biological Markers Biology Carcinoma Characteristics Clinical Copy Number Polymorphism DNA Damage Data Deglutition Development Disease Distant Distant Metastasis Etiology Event Failure Future Gene Expression Genes Genetic Genetic Transcription Genome Goals HPV-High Risk Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Head and neck structure Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Incidence Infection Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of larynx Mediating Molecular Molecular Abnormality Molecular Target Morbidity - disease rate Mutation Neoplasm Metastasis Neuropathy Oncogenes Oncogenic Viruses Oropharyngeal Oropharyngeal Head and Neck Squamous Cell Carcinoma Oropharyngeal Squamous Cell Carcinoma Other Genetics Outcome Pathway interactions Patients Precision medicine trial RNA Splicing Radiation Recurrence Resistance Risk Role Series Site Squamous Cell TP53 gene Testing Tobacco Tonsil Transcript United States Variant Viral Viral Genes Viral Oncogene Virus Virus Integration Work aggressive therapy alternative treatment behavioral outcome behavioral response chemotherapy cigarette smoking design falls gene function high risk human papilloma virus oncogene improved outcome individualized medicine integration site interest malignant mouth neoplasm malignant oropharynx neoplasm malignant tongue neoplasm malignant tonsil neoplasm outcome prediction patient subsets personalized medicine precision medicine predict clinical outcome programs public health relevance response side effect therapeutic target tongue root tumor tumor behavior tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Oropharyngeal cancer has been increasing in incidence in the United States since 1970, while other head and neck cancers are becoming less common. The factors responsible for this change are: 1) infection with high risk human papillomaviruses (hrHPV) leading to virally-induced tonsil and base of tongue cancers and; 2) reduced cigarette smoking that is beginning to have an impact on the incidence of oral and laryngeal cancer. Most HPV-positive oropharynx cancers respond well to intensive therapy consisting of concurrent chemotherapy and intensity modulated radiation (IMRT). The high response rate (70-80% in most series) and the high morbidity (swallowing problems and neuropathies) of current therapy have stimulated interest in deescalating treatment intensity for HPV-positive oropharynx cancers. Notably, even with intensive treatment 20-30% of the patients progress to lethal recurrent or metastatic disease. The excellent response rates may fall substantially with less aggressive treatment. Thus, it is critical to understand the molecular mechanisms that determine tumor behavior and response to therapy. We will test these hypotheses: 1) we postulate that tumors driven predominantly by the HPV oncogenes, E6 and E7, are those tumors most likely to be managed by low morbidity strategies; 2) we postulate that HPV integration within a cellular gene increases the risk of recurrent and metastatic disease; and 3) we postulate that HPV-positive tumors that have additional genetic aberrations are the most resistant to current therapy and will require alternative treatment. Thus, we are investigating molecular characteristics of the tumor, the virus and the cellular genome of HPV-induced cancers to determine those factors that identify the genetic characteristics that differentiate tumors that progress from those that respond, and to identify targetable molecular changes. We postulate that tumors driven only by the viral oncogenes may be susceptible to a variety of low morbidity treatments. Integration into a cancer related gene may increase likelihood of progression but may also identify a potentially targetable pathway. Tumors with additional molecular drivers or lost control mechanisms may be the most likely to recur or metastasize, but may also have targetable pathways. These concepts can be tested by future trials once the biomarkers are known. In this project we will investigate HPV integration site, viral oncogene expression and alternate transcripts, effects of integration on cellular gene expression, and we will characterize other genetic abnormalities that correlate with outcome. Preliminary data support our hypotheses and from this work we hope to develop individualized treatment most appropriate for each patient with HPV-positive oropharyngeal cancer.

描述（由适用提供）：自1970年以来，美国口咽癌的发病率一直在增加，而其他头颈癌的发病率也变得不那么普遍。导致这种变化的因素是：1）感染具有高风险的人乳头瘤病毒（HRHPV），导致几乎引起的扁桃体和舌癌的基础感染； 2）减少吸烟，这开始对口腔和喉癌事件产生影响。大多数HPV阳性口咽癌对由同时进行化学疗法和强度调节辐射（IMRT）组成的强化疗法的反应很好。当前疗法的高反应率（大多数系列中为70-80％）和高发病率（吞咽问题和神经病）刺激了HPV阳性口咽癌的深度钙化治疗强度的兴趣。值得注意的是，即使接受密集治疗，有20-30％的患者会发展为致命的复发或转移性疾病。出色的回应率可能会大大下降，而积极的治疗较少。那是至关重要的决定肿瘤行为和对治疗反应的机制。我们将检验这些假设：1）我们假设肿瘤主要由HPV Oncogenes E6和E7驱动，是这些肿瘤最有可能由低发病策略控制的肿瘤。 2）我们假设细胞基因内的HPV整合会增加复发和转移性疾病的风险； 3）我们假设具有其他遗传畸变的HPV阳性肿瘤我们假设，只有病毒癌基因驱动的肿瘤可能会易于多种发病率处理。与癌症相关的基因的整合可能会增加进展的可能性，但也可能识别出潜在的靶向途径。具有其他分子驱动因素或丢失的控制机制的肿瘤可能最有可能复发或转移，但也可能具有可靶向的途径。一旦已知生物标志物，就可以通过未来的试验来测试这些概念。在该项目中，我们将研究HPV整合位点，病毒性癌基因表达和替代转录本，整合对细胞基因表达的影响，我们将表征与结果相关的其他遗传异常。初步数据支持我们的假设，从这项工作中，我们希望开发最适合每个患有HPV阳性口咽癌患者的个性化治疗方法。