Molecular Mechanisms of Tumor Behavior and Response to Therapy in HPV-positive Oropharyngeal Cancer

HPV 阳性口咽癌肿瘤行为和治疗反应的分子机制

• 批准号: 10370443
• 负责人: THOMAS E. CAREY
• 金额: $ 8.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370443
• 关键词: Advocate; Affect; Aftercare; Alcohols; Alternative Therapies; Behavior; Biological Markers; Biology; Carcinoma; Characteristics; Clinical; Copy Number Polymorphism; DNA Damage; Data; Deglutition; Development; Disease; Distant; Distant Metastasis; Etiology; Event; Failure; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; HPV-High Risk; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Incidence; Infection; Lesion; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of larynx; Mediating; Molecular; Molecular Abnormality; Molecular Target; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Neuropathy; Oncogenes; Oncogenic Viruses; Oropharyngeal; Oropharyngeal Head and Neck Squamous Cell Carcinoma; Oropharyngeal Squamous Cell Carcinoma; Other Genetics; Outcome; Pathway interactions; Patients; Precision medicine trial; RNA Splicing; Radiation; Recurrence; Resistance; Risk; Role; Series; Site; Squamous Cell; TP53 gene; Testing; Tobacco; Tonsil; Transcript; United States; Variant; Viral; Viral Genes; Viral Oncogene; Virus; Virus Integration; Work; aggressive therapy; alternative treatment; behavioral outcome; behavioral response; chemotherapy; cigarette smoking; design; falls; gene function; high risk; human papilloma virus oncogene; improved outcome; individualized medicine; integration site; interest; malignant mouth neoplasm; malignant oropharynx neoplasm; malignant tongue neoplasm; malignant tonsil neoplasm; outcome prediction; patient subsets; personalized medicine; precision medicine; predict clinical outcome; programs; public health relevance; response; side effect; therapeutic target; tongue root; tumor; tumor behavior; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Oropharyngeal cancer has been increasing in incidence in the United States since 1970, while other head and neck cancers are becoming less common. The factors responsible for this change are: 1) infection with high risk human papillomaviruses (hrHPV) leading to virally-induced tonsil and base of tongue cancers and; 2) reduced cigarette smoking that is beginning to have an impact on the incidence of oral and laryngeal cancer. Most HPV-positive oropharynx cancers respond well to intensive therapy consisting of concurrent chemotherapy and intensity modulated radiation (IMRT). The high response rate (70-80% in most series) and the high morbidity (swallowing problems and neuropathies) of current therapy have stimulated interest in deescalating treatment intensity for HPV-positive oropharynx cancers. Notably, even with intensive treatment 20-30% of the patients progress to lethal recurrent or metastatic disease. The excellent response rates may fall substantially with less aggressive treatment. Thus, it is critical to understand the molecular mechanisms that determine tumor behavior and response to therapy. We will test these hypotheses: 1) we postulate that tumors driven predominantly by the HPV oncogenes, E6 and E7, are those tumors most likely to be managed by low morbidity strategies; 2) we postulate that HPV integration within a cellular gene increases the risk of recurrent and metastatic disease; and 3) we postulate that HPV-positive tumors that have additional genetic aberrations are the most resistant to current therapy and will require alternative treatment. Thus, we are investigating molecular characteristics of the tumor, the virus and the cellular genome of HPV-induced cancers to determine those factors that identify the genetic characteristics that differentiate tumors that progress from those that respond, and to identify targetable molecular changes. We postulate that tumors driven only by the viral oncogenes may be susceptible to a variety of low morbidity treatments. Integration into a cancer related gene may increase likelihood of progression but may also identify a potentially targetable pathway. Tumors with additional molecular drivers or lost control mechanisms may be the most likely to recur or metastasize, but may also have targetable pathways. These concepts can be tested by future trials once the biomarkers are known. In this project we will investigate HPV integration site, viral oncogene expression and alternate transcripts, effects of integration on cellular gene expression, and we will characterize other genetic abnormalities that correlate with outcome. Preliminary data support our hypotheses and from this work we hope to develop individualized treatment most appropriate for each patient with HPV-positive oropharyngeal cancer.

 描述(申请人提供)：自1970年以来，口咽癌在美国的发病率一直在上升，而其他头颈部癌症正在变得不那么常见。导致这一变化的因素是：1)感染高危人乳头瘤病毒(HrHPV)导致病毒诱导的扁桃体和舌根癌；2)减少吸烟，这开始对口腔和喉癌的发病率产生影响。大多数HPV阳性的口咽癌对同时化疗和调强放疗(IMRT)的强化治疗反应良好。目前治疗HPV阳性口咽癌的高有效率(大多数系列为70-80%)和高发病率(吞咽问题和神经病变)激发了降低HPV阳性口咽癌治疗强度的兴趣。值得注意的是，即使进行强化治疗，仍有20%-30%的患者进展为致命的复发或转移性疾病。如果治疗不那么积极，显效率可能会大幅下降。因此，了解分子水平是至关重要的。 决定肿瘤行为和治疗反应的机制。我们将检验这些假设：1)我们假设主要由HPV癌基因E6和E7驱动的肿瘤是那些最有可能通过低发病率策略进行管理的肿瘤；2)我们假设HPV在细胞基因中的整合增加了复发和转移疾病的风险；以及3)我们假设具有额外基因异常的HPV阳性肿瘤对当前的治疗最具抵抗力，将需要替代治疗。因此，我们正在研究肿瘤、病毒和HPV诱导的癌症细胞基因组的分子特征，以确定那些识别区分进展的肿瘤和有效的肿瘤的遗传特征的因素，并确定有针对性的分子变化。我们推测，仅由病毒癌基因驱动的肿瘤可能对各种低发病率治疗敏感。整合到癌症相关基因中可能会增加进展的可能性，但也可能识别潜在的靶向途径。带有额外分子驱动因素或失去控制机制的肿瘤可能最有可能复发或转移，但也可能有靶向通路。一旦知道了生物标志物，这些概念就可以通过未来的试验进行测试。在这个项目中，我们将研究HPV整合位点、病毒癌基因表达和交替转录本、整合对细胞基因表达的影响，并将描述与结果相关的其他遗传异常。初步数据支持我们的假设，我们希望从这项工作中开发出最适合每个HPV阳性口咽癌患者的个体化治疗方法。

项目成果

Understanding the impact of high-risk human papillomavirus on oropharyngeal squamous cell carcinomas in Taiwan: A retrospective cohort study.

• DOI: 10.1371/journal.pone.0250530
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Lorenzatti Hiles G;Chang KP;Bellile EL;Wang CI;Yen WC;Goudsmit CM;Briggs HL;Thomas TB;Peters L;Afsari MA;Pinatti LM;Morris AC;Jawad N;Carey TE;Walline HM
• 通讯作者: Walline HM

Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma.

• DOI: 10.1002/hed.27018
• 发表时间: 2022-05
• 期刊: Head & neck
• 作者: Michmerhuizen NL;Ludwig ML;Birkeland AC;Nimmagadda S;Zhai J;Wang J;Jewell BM;Genouw D;Remer L;Kim D;Foltin SK;Bhangale A;Kulkarni A;Bradford CR;Swiecicki PL;Carey TE;Jiang H;Brenner JC
• 通讯作者: Brenner JC

Biospecimens, Research Consent, and Distinguishing Cell Line Research.

生物样本、研究同意书和区分细胞系研究。

• DOI: 10.1001/jamaoncol.2018.6988
• 发表时间: 2019
• 期刊: JAMA oncology
• 影响因子: 28.4
• 作者: Spector-Bagdady,Kayte;FernandezLynch,Holly;Brenner,JChad;Shuman,AndrewG
• 通讯作者: Shuman,AndrewG

SearcHPV: A novel approach to identify and assemble human papillomavirus-host genomic integration events in cancer.

• DOI: 10.1002/cncr.33691
• 发表时间: 2021-10-01
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Pinatti LM;Gu W;Wang Y;Elhossiny A;Bhangale AD;Brummel CV;Carey TE;Mills RE;Brenner JC
• 通讯作者: Brenner JC

Great Lakes Biorepository Research Network's Annual Biobanking Symposium: A Focus on Precision Medicine.

五大湖生物样本库研究网络年度生物样本库研讨会：聚焦精准医学。

• DOI: 10.1089/bio.2019.0022
• 发表时间: 2019
• 期刊: Biopreservation and biobanking
• 影响因子: 1.6
• 作者: Paulauskis,JosephD;Blanc,VictoriaM;Carey,Thomas;Chesla,DavidW;Frey,RenéeC;Geddes,Timothy;Keats,Jonathan;Loup,Allan;Pruetz,Barbara;Rohrer,DanielC;Valley,DanaR;Tomlinson,Tom;Akervall,Jan;Wilson,GeorgeD;Jewell,ScottD
• 通讯作者: Jewell,ScottD