Head and Neck squamous cell carcinoma radiation response modulation by HPV

HPV 调节头颈鳞状细胞癌放射反应

基本信息

批准号：
8165405
负责人：
RANDALL J KIMPLE
金额：
$ 14.9万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-05 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8165405
关键词：
Age Alcohols Apoptotic Award Biological Models Biology Cell Line Cell physiology Cells Clinical Clinical Research Clinical Trials Complex Conflict (Psychology)Development Disease Down-Regulation EGFR Protein Overexpression Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Family member Future Genes Goals Grant Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Human Papillomavirus Human papilloma virus infection Incidence Ionizing radiation JUN gene Lead Learning Link Malignant Epithelial Cell Malignant Neoplasms Mediating Membrane Proteins Mentors Molecular Molecular Virology Outcome Pathway interactions Patients Phase Play Primary Neoplasm Principal Investigator Protein p53 Protein phosphatase Proteins Public Health Radiation Radiation Tolerance Radiation-Sensitizing Agents Radiosensitization Receptor Inhibition Receptor Signaling Reporting Research Role Scaffolding Protein Signal Pathway Staging Techniques Tobacco Toxic effect Training Transgenic Mice Transgenic Model Tumor Suppressor Proteins Up-Regulation Viral Genes Viral Proteins Virus Diseases Work base career development cdc Genes chemotherapy clinical care design effective therapy experience genetic profiling improved member mouse model next generation novel outcome forecast patient population programs protein expression receptor expression response therapy development treatment response trial comparing tumor tumor xenograft virology

项目摘要

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.

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严重的公共卫生问题。与传统的烟草和酒精相关的头颈鳞状细胞癌 (HNSCC) 患者相比，这些患者的发病年龄通常更年轻，并且疾病处于晚期。矛盾的是，这些 HPV 相关肿瘤的生存结果显着改善。这些改善结果的机制仍不清楚。独立之路奖中提出的工作有两个主要目标：1）促进首席研究员（PI）的职业发展，并帮助建立他的独立性，领导一项调查病毒相关癌症辐射反应的研究项目； 2) 了解 HPV 相关 HNSCC 在对放疗和化疗的反应方面与传统 HNSCC 有何不同。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方面的额外培训。在指导阶段进行的研究将研究为什么 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 表达水平低。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 丢失对放射增敏策略的影响。这些研究将提供关于放射和化疗敏感性增加的机制的新线索，并可能确定治疗开发的重要新靶标，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) 感染相关的头颈鳞状细胞癌在全球发病率迅速增加，通常已处于晚期，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，旨在确定放射增敏的新方法、表皮生长因子受体（EGFR）信号传导与放射增敏之间的关系以及放射增敏的潜在新机制。最终目标是设计放疗和化疗的合理组合，以进一步改善结果和/或降低治疗毒性。