Pursuing molecular biomarkers to guide adjuvant therapy for HPV+ head and neck cancers after transoral robotic surgery

寻找分子生物标志物来指导经口机器人手术后 HPV 头颈癌的辅助治疗

• 批准号: 10357120
• 负责人: Devraj Basu
• 金额: $ 26.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357120
• 关键词: Adjuvant; Adjuvant Therapy; Adoption; Archives; Biological Markers; Chemotherapy and/or radiation; Cisplatin; Clinical Trials Design; Data; Discrimination; Disease; Distant; Gene Expression; Genes; Genetic; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Incidence; Knowledge; Longterm Follow-up; Metabolic; Modeling; Modernization; Molecular; Oncogenes; Operative Surgical Procedures; Oropharyngeal; Outcome; Patients; Pattern; Prognosis; Prognostic Marker; Proteins; Radiation Dose Unit; Recurrence; Relapse; Risk; Robotics; Somatic Mutation; Specimen; Survivors; Testing; Time; Toxic effect; Treatment Failure; Up-Regulation; Validation; Viral; Viral Genes; Viral Genome; base; case control; cohort; differential expression; disability; exome sequencing; follow-up; genetic variant; genome sequencing; high risk; improved; individual patient; molecular marker; novel; novel therapeutics; prevent; prospective; safe patient; side effect; tool; trait; transcriptomics; treatment optimization; treatment response; tumor

PROJECT SUMMARY This proposal aims to optimize therapy for human papilloma virus-related (HPV+) squamous cell carcinomas of the head and neck (HNSCCs), which are rapidly increasing in incidence. The relatively favorable prognosis for the HPV+ subtype of HNSCC has justified ongoing efforts to de-intensify their treatment with high dose radiation and cisplatin, whose toxicities can leave lifelong disabilities in survivors. A recently popularized approach to therapy de-escalation is transoral robotic surgery (TORS), which has markedly altered practice patterns for this disease and allowed for reduction in cisplatin use and radiation dosing relative to nonsurgical therapy. However, poor ability to stratify recurrence risk after TORS is a key barrier to both safely de-escalating adjuvant therapy for typical HPV+ HNSCCs and intensifying treatment for certain cases that are predisposed to lethal outcome. This proposal seeks to fill this knowledge gap by leveraging a unique set of archival HPV+ HNSCC specimens from patients treated by TORS to pursue novel molecular biomarkers of treatment response and prognosis. Our studies of older cohorts with widely variable treatment suggest worse outcomes for HPV+ HNSCCs with high oxidative metabolic gene expression, reduced E2F target gene upregulation, and lower viral E6 oncogene expression. Thus, our overall hypothesis is that genetic variants and expression profiles of both host and viral genes will allow prospective discrimination of HPV+ HNSCCs at risk of lethal outcome after TORS-based therapy. To test this hypothesis, Aim 1 will identify host and viral expression profiles distinguishing HPV+ HNSCCs that recur after TORS. Case-control analyses will be applied to a cohort of 634 TORS-treated HPV+ HNSCCs with uniquely long-term follow-up in order to identify viral and host genes differentially expressed in tumors that later recurred. Recurrent cases will be matched to nonrecurrent controls based on stage, adjuvant therapy, and follow-up. Transcriptomic analysis will be followed by protein level validation for select differentially expressed genes. Aim 2 will define genetic traits of HPV+ HNSCCs that recur after TORS and pursue a multi-marker stratifier of recurrence risk. Whole exome sequencing will be used to identify somatic mutations and copy number alterations that distinguish tumors that recurred from nonrecurrent controls. In addition, viral genome sequencing will be used to assess for viral subtypes, sub-lineages, and nonsynonymous SNPs that are over-represented in recurrence-prone tumors. Genetic traits associated with treatment failure will be integrated with transcriptomic data to develop a multi-marker signature that stratifies HPV+ HNSCCs for lethal recurrence risk. This assessment of molecular traits that distinguish tumors with high recurrence risk after TORS-based therapy will create a discrete panel of molecular features that can be tested in large cohorts, leading to creation of strong prognostic biomarkers under a modern treatment paradigm for HPV+ HNSCC. Such tools would dramatically enhance clinical trial design by identifying easily curable patients for safe reduction in adjuvant therapy and patients at high risk of treatment failure for testing of novel therapies.

项目摘要 该提案旨在优化人乳头状瘤病毒相关（HPV+）鳞状细胞癌的治疗， 头部和颈部（HNSCC），其发病率迅速增加。相对有利的预后， HNSCC的HPV+亚型证明了正在进行的降低高剂量治疗强度的努力是合理的 放射和顺铂，其毒性可能会使幸存者终身残疾。最近流行的 治疗降级的方法是经口机器人手术（TORS），它显著改变了实践 这种疾病的模式，并允许减少顺铂的使用和放射剂量相对于非手术 疗法然而，TORS后复发风险分层能力差是安全降级的关键障碍 典型HPV+ HNSCC的辅助治疗和某些易患HPV + HNSCC的病例的强化治疗 致命的结果。该提案旨在通过利用一套独特的HPV+档案来填补这一知识空白。 来自TORS治疗患者的HNSCC标本，以寻求新的治疗分子生物标志物 反应和预后。我们对年龄较大的队列进行的研究表明，治疗方法差异很大，结果更差 对于具有高氧化代谢基因表达的HPV+ HNSCC，E2F靶基因上调降低，以及 降低病毒E6癌基因表达。因此，我们的总体假设是，遗传变异和表达 宿主基因和病毒基因的谱将允许前瞻性区分具有致死风险的HPV+ HNSCC。 基于TORS的治疗后的结果。为了验证这一假设，目标1将确定宿主和病毒表达 区分TORS后复发的HPV+ HNSCC的特征。将对队列进行病例对照分析 对634例TORS治疗的HPV+ HNSCC进行独特的长期随访，以确定病毒和宿主基因 在肿瘤中的差异表达。复发病例将与非复发对照组相匹配 根据分期、辅助治疗和随访。转录组学分析之后将进行蛋白质水平 验证选择的差异表达基因。目的2将定义复发的HPV+ HNSCC的遗传特征， TORS后，并追求复发风险的多标记分层。全外显子组测序将用于 鉴定区分肿瘤复发和非复发的体细胞突变和拷贝数改变 对照此外，病毒基因组测序将用于评估病毒亚型、亚系和 在复发倾向性肿瘤中过度表达的非同义SNP。遗传特征与 治疗失败将与转录组学数据相结合，以开发一种多标记物特征， HPV+ HNSCC的致命复发风险。这种对区分肿瘤与高分化肿瘤的分子特征的评估， 基于TORS的治疗后的复发风险将产生一组离散的分子特征， 在大型队列中，导致在现代治疗模式下产生强预后生物标志物， HPV+ HNSCC。这些工具将通过识别容易治愈的患者来显著增强临床试验设计 用于安全减少辅助治疗和用于测试新疗法的治疗失败的高风险患者。