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.

项目概要 该提案旨在优化人乳头瘤病毒相关（HPV+）鳞状细胞癌的治疗 头颈部 (HNSCC) 的发病率正在迅速增加。相对有利的预后 HNSCC 的 HPV+ 亚型证明了持续努力降低高剂量治疗强度的合理性 辐射和顺铂，其毒性可能导致幸存者终身残疾。最近流行的一个 治疗降级的方法是经口机器人手术（TORS），它显着改变了实践 与非手术治疗相比，可以减少顺铂的使用和放射剂量 治疗。然而，TORS 后复发风险分层能力差是安全降级的关键障碍 针对典型 HPV+ HNSCC 的辅助治疗以及针对某些易患 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档案 HPV+ 来填补这一知识空白 来自接受 TORS 治疗的患者的 HNSCC 标本，以寻求新的治疗分子生物标志物 反应和预后。我们对治疗方法差异较大的老年群体的研究表明结果更差 对于具有高氧化代谢基因表达、减少 E2F 靶基因上调的 HPV+ HNSCC，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 宿主和病毒基因的概况将允许前瞻性地区分具有致命风险的 HPV+ HNSCC 基于 TORS 的治疗后的结果。为了检验这一假设，目标 1 将识别宿主和病毒表达 特征可区分 TORS 后复发的 HPV+ HNSCC。病例对照分析将应用于队列 对 634 个经 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 在随后复发的肿瘤中差异表达。复发病例将与非复发对照相匹配 基于分期、辅助治疗和随访。转录组分析之后是蛋白质水平 验证选择差异表达基因。目标 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 识别体细胞突变和拷贝数改变，以区分复发性肿瘤和非复发性肿瘤 控制。此外，病毒基因组测序将用于评估病毒亚型、亚谱系和 在易复发的肿瘤中过多出现的非同义 SNP。相关遗传性状 治疗失败将与转录组数据整合，以开发分层的多标记特征 HPV+ HNSCC 具有致命的复发风险。这种对区分肿瘤的分子特征的评估具有高 基于 TORS 的治疗后的复发风险将创建一组可测试的离散分子特征 在大型队列中，导致在现代治疗范式下创建强预后生物标志物 HPV+ HNSCC。这些工具将通过识别易于治愈的患者来显着增强临床试验设计 用于安全减少辅助治疗和治疗失败高风险患者测试新疗法。