Head and Neck squamous cell carcinoma radiation response modulation by HPV

描述（由申请人提供）：人乳头瘤病毒（HPV）相关的头颈癌是一个日益增长的公共卫生问题。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。奇怪的是，这些HPV相关肿瘤显示出显著改善的生存结局。这些改善结果的机制仍不清楚。这项独立之路奖中提出的工作有两个主要目标：1）促进主要研究者（PI）的职业发展，并帮助建立他的独立性，以领导一项研究病毒相关癌症的放射反应的研究计划; 2）了解HPV相关HNSCC与传统HNSCC在放射和化疗反应方面的差异。在研究的指导阶段，PI将获得分子病毒学，人乳头瘤病毒生物学和小鼠癌症模型的额外培训。在指导阶段进行的研究将检查为什么HPV相关的HNSCC比传统的HNSCC对放疗和化疗更敏感，并检查表皮生长因子受体（EGFR）抑制剂使HPV相关的头颈癌对放疗敏感的能力，尽管EGFR表达水平较低。在独立阶段，研究将检查HPV病毒蛋白对EGFR受体介导的放射增敏作用的影响以及EGFR丢失对放射增敏策略的影响。这些研究将提供关于对放疗和化疗敏感性增加的机制的新线索，并可能为治疗开发确定重要的新靶点，以进一步改善HPV相关和非HPV相关头颈癌患者的预后。 公共卫生相关性：与人乳头瘤病毒（HPV）感染相关的头颈部鳞状细胞癌在全球发病率迅速增加，通常出现在晚期，通常采用放疗和化疗治疗，并且通常显示出改善的预后;然而，最佳治疗的选择仍然不明确。该提案研究了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）信号传导与放射敏感性之间的关系，以及放射增敏的潜在新机制。最终目的是设计合理的放疗和化疗组合，以进一步改善结局和/或降低治疗毒性。

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.