Head and Neck squamous cell carcinoma radiation response modulation by HPV

描述(申请人提供)：人类乳头瘤病毒(HPV)相关的头颈部癌症是一个日益严重的公共卫生问题。这些患者通常比传统的烟草和酒精相关的头颈部鳞状细胞癌(HNSCC)患者年龄更小，疾病更晚期。矛盾的是，这些与HPV相关的肿瘤显示出显著改善的生存结果。这些改善结果背后的机制仍不清楚。独立之路奖建议的工作有两个主要目标：1)促进首席研究员(PI)的职业发展，并帮助他建立领导一个研究病毒相关癌症辐射反应的研究计划的独立性；以及2)了解HPV相关性HNSCC在放射和化疗反应方面与传统HNSCC的不同之处。在研究的指导阶段，PI将在分子病毒学、人类乳头瘤病毒生物学和癌症的小鼠模型方面获得额外的培训。在指导阶段进行的这项研究将研究为什么HPV相关的HNSCC比传统的HNSCC对放射和化疗更敏感，并检查尽管表皮生长因子受体(EGFR)表达水平较低，但表皮生长因子受体(EGFR)抑制剂仍能使HPV相关的头颈部癌症对辐射敏感。在独立阶段，研究将检查HPV病毒蛋白对EGFR抑制剂介导的放射增敏的影响，以及EGFR缺失对放射增敏策略的影响。这些研究将提供有关增加对放射和化疗敏感性的机制的新线索，并可能为治疗开发确定重要的新靶点，以进一步改善HPV相关性和非HPV相关性头颈癌患者的预后。 与公共卫生相关：与人类乳头瘤病毒(HPV)感染相关的头颈部鳞状细胞癌在全球发病率迅速上升，通常出现在晚期，通常采用放射和化疗治疗，通常显示预后改善；然而，最佳治疗方案的选择仍未确定。这项建议研究治疗反应的分子机制，目的是确定放射增敏的新方法，表皮生长因子受体(EGFR)信号与放射敏感性之间的关系，以及潜在的放射增敏新机制。最终目标是设计合理的放射和化疗组合，以进一步改善结果和/或减少治疗毒性。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) associated head and neck cancer is a growing public health concern. These patients commonly present at a younger age and with more advanced stage disease than patients with traditional tobacco and alcohol associated head and neck squamous cell carcinoma (HNSCC). Paradoxically, these HPV-associated tumors show notably improved survival outcomes. Mechanisms underlying these improved outcomes remain unclear. The work proposed in this Pathways to Independence Award has two primary goals: 1) to facilitate career development of the principal investigator (PI) and to help establish his independence to lead a research program investigating radiation response in virally associated cancers; and, 2) to understand how HPV-associated HNSCC differs from traditional HNSCC in response to radiation and chemotherapy. During the mentored phase of research, the PI will obtain additional training in molecular virology, human papillomavirus biology, and mouse models of cancer. The research conducted during the mentored phase will examine why HPV-associated HNSCC are more sensitive than traditional HNSCC to radiation and chemotherapy and to examine the ability of epidermal growth factor receptor (EGFR) inhibitors to sensitize HPV-associated head and neck cancer to radiation despite low levels of EGFR expression. During the independent phase, research will examine the impact of HPV viral proteins on EGFR inhibitor-mediated radiosensitization and the impact of EGFR loss on radiosensitization strategies. These studies will provide new clues regarding mechanisms of increased sensitivity to radiation and chemotherapy and may identify important new targets for therapy development to further improve outcome for patients with both HPV-associated and non-HPV-associated head and neck cancer. PUBLIC HEALTH RELEVANCE: Head and neck squamous cell carcinomas associated with human papillomavirus (HPV) infection are rapidly increasing in global incidence, often present at an advanced stage, are commonly treated with radiation and chemotherapy, and generally show an improved prognosis; nevertheless, selection of optimal therapy remains ill defined. This proposal investigates molecular mechanisms of treatment response with a goal to identify novel means of radiosensitization, the relationship between epidermal growth factor receptor (EGFR) signaling and radiosensitivity, and potential novel mechanisms of radiosensitization. The ultimate objective is to design rationale combinations of radiation and chemotherapy to further improve outcome and/or decrease treatment toxicity.