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

 描述（由申请人提供）：自1970年以来，口咽癌在美国的发病率一直在增加，而其他头颈部癌症正变得越来越不常见。导致这种变化的因素是：1）感染高危人乳头瘤病毒（hrHPV），导致病毒诱导的扁桃体和舌根癌; 2）减少吸烟，开始对口腔癌和喉癌的发病率产生影响。大多数HPV阳性口咽癌对由同步化疗和调强放疗（IMRT）组成的强化治疗反应良好。目前治疗的高应答率（大多数系列中为70-80%）和高发病率（吞咽问题和神经病变）激发了降低HPV阳性口咽癌治疗强度的兴趣。值得注意的是，即使采用强化治疗，也有20-30%的患者进展为致命的复发性或转移性疾病。治疗积极性较低的患者，其极好的缓解率可能会大幅下降。因此，了解分子的 决定肿瘤行为和对治疗反应的机制。我们将测试这些假设：1）我们假设主要由HPV致癌基因E6和E7驱动的肿瘤是最有可能通过低发病率策略管理的那些肿瘤; 2）我们假设细胞基因内的HPV整合增加复发和转移性疾病的风险; 3）我们假设HPV-具有额外遗传畸变的阳性肿瘤对当前疗法最具抗性，并且将需要替代治疗。因此，我们正在研究HPV诱导的癌症的肿瘤、病毒和细胞基因组的分子特征，以确定那些识别遗传特征的因素，这些遗传特征将进展的肿瘤与有反应的肿瘤区分开来，并识别可靶向的分子变化。我们推测，仅由病毒致癌基因驱动的肿瘤可能对各种低发病率治疗敏感。整合到癌症相关基因中可以增加进展的可能性，但也可以鉴定潜在的靶向途径。具有额外分子驱动或失去控制机制的肿瘤可能最有可能复发或转移，但也可能具有靶向途径。一旦生物标志物已知，这些概念可以通过未来的试验进行测试。在这个项目中，我们将研究HPV整合位点，病毒癌基因表达和替代转录，整合对细胞基因表达的影响，我们将描述与结果相关的其他遗传异常。初步的数据支持我们的假设，从这项工作中，我们希望开发出最适合每个HPV阳性口咽癌患者的个性化治疗。

 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.