Head and Neck squamous cell carcinoma radiation response modulation by HPV

项目总结/摘要 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 患者通常出现在较年轻的年龄和更先进的阶段的疾病比患者 传统的烟草和酒精相关的头颈部鳞状细胞癌（HNSCC）。巧合的是， 这些HPV相关肿瘤显示出显著改善的存活结果。这些问题背后的机制 改善的结果仍不清楚。在这个独立之路奖提出的工作有两个 主要目标：1）促进主要研究者（PI）的职业发展， 独立领导一项研究计划，调查病毒相关癌症的辐射反应;以及， 2)了解HPV相关HNSCC与传统HNSCC在对辐射的反应方面的不同， 化疗在研究的指导阶段，PI将获得分子生物学方面的额外培训， 病毒学、人乳头瘤病毒生物学和癌症小鼠模型。在此期间进行的研究 指导阶段将研究为什么HPV相关的HNSCC比传统的HNSCC更敏感， 并检查表皮生长因子受体（EGFR）抑制剂的能力， 尽管EGFR表达水平较低，但HPV相关头颈癌对放射敏感。期间 在独立阶段，研究将检查HPV病毒蛋白对EGFR介导的 放射增敏和EGFR丢失对放射增敏策略的影响。这些研究将提供新的 关于对放疗和化疗敏感性增加的机制的线索， 治疗开发的新靶点，以进一步改善HPV相关和 非HPV相关的头颈癌。

Project Summary/Abstract 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.