Determining the impact of ancestry on oropharyngeal cancer biology and treatment response.

确定血统对口咽癌生物学和治疗反应的影响。

• 批准号: 10562456
• 负责人: GERMAN CORREDOR
• 金额: $ 26.32万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562456
• 关键词: Address; African American; Biological; Cancer Biology; Cancer Patient; Characteristics; Classification; Clinical; Clinical Data; County Hospitals; Data; Data Set; Development; Disease; Disparity; Environmental Exposure; Equity; Exhibits; Frequencies; Gene Expression Profile; Genes; Genomics; Head and Neck Cancer; Health Services Accessibility; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Immune checkpoint inhibitor; Inferior; Institution; Integration Host Factors; Link; Machine Learning; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of urinary bladder; Measures; Medical center; Metastatic/Recurrent; Molecular Analysis; Outcome; Patient Self-Report; Patients; Physicians; Population; Pre-Clinical Model; Progression-Free Survivals; Publishing; Race; Regional Cancer; Reproducibility; Risk; Single Nucleotide Polymorphism; Smoker; Smoking; Smoking History; Societies; Spatial Distribution; Specimen; T-cell inflamed; Testing; Time; Tissue-Specific Gene Expression; Tobacco; Tumor Biology; Tumor-Infiltrating Lymphocytes; United States; United States Department of Veterans Affairs; Validation; advanced disease; behavioral response; cancer care; cancer diagnosis; cancer survival; cancer therapy; care delivery; clinical translation; cohort; conventional therapy; design; differential expression; disparity reduction; effective therapy; high throughput analysis; histological slides; improved; malignant oropharynx neoplasm; neoplastic cell; non-smoker; novel; patient population; precision oncology; racial disparity; response; socioeconomics; standard of care; transcriptomics; treatment response; tumor; tumor-immune system interactions; tumorigenesis

ABSTRACT Oropharyngeal cancer (OPC) is now the most common malignancy of the head and neck region, and OPC associated with the human papillomavirus (HPV) has overtaken cervical cancer as the most common HPV- associated malignancy in the United States. African American (AA) patients demonstrate inferior OPC oncologic outcomes to their non-AA counterparts even when adjusting for HPV effect. It is not known whether reduced treatment response and survival in AA OPC patients is driven solely by unequitable access to care and other socio-economic variables or whether it is impacted at least partially by the interaction between ancestry and cancer biology. No previous study has addressed this question using an adequate OPC clinical dataset with correlative genomic and transcriptomic data in order to address this translationally important question. Therefore, it is not possible to determine whether OPC treatment response and survival in AA patients is partially linked to differential tumor biology using existing datasets. In this application, we will utilize two unique OPC cohorts enriched for AA patients to test the hypothesis that OPC development in AA patients is accompanied by more aggressive tumor biology facilitated by an immunosuppressive tumor immune microenvironment (TIME). In Aim 1 we will correlate self-reported race and calculated ancestry to intrinsic OPC tumor biology and treatment response. Specifically, we will test the correlation between tumor cell multi-nucleation (a feature of aggressive OPC biology recently validated by our team in a multi-institutional OPC cohort), survival, and differential gene expression in AA OPC patients matched to their non-AA counterparts for T classification, HPV status, and smoking history. In Aim 2 we will correlate self- reported race and calculated ancestry to changes in TIME and treatment response in previously untreated AA OPC patients as well as immune checkpoint inhibitor response in AA OPC patients with recurrent/metastatic disease. For both sets of analyses, we will deploy novel, validated machine learning approaches to analysis of conventional histologic slides designed to facilitate rapid clinical translation across multiple other institutions. Completion of the proposed studies will, for the first time, establish the link between race/ancestry, OPC biological behavior, and treatment response. Successful validation of our hypothesis will provide a unique opportunity for the development of precision oncology approaches to AA OPC management aimed at reversing the disparities noted in cancer specific survival for this understudied patient population.

摘要 口咽癌（OPC）现在是头颈部最常见的恶性肿瘤， 与人乳头瘤病毒（HPV）相关的OPC已超过宫颈癌，成为最常见的HPV- 相关恶性肿瘤。非裔美国人（AA）患者表现出较差的OPC肿瘤学 即使在调整HPV效应时，其结果也与非AA对应物相同。目前尚不清楚是否减少 AA OPC患者的治疗反应和生存率完全由不公平的护理和其他因素驱动。 社会经济变量或是否至少部分受到祖先和 癌症生物学以前没有研究使用足够的OPC临床数据集解决这个问题， 相关的基因组和转录组数据，以解决这个至关重要的问题。因此，我们认为， 不可能确定OPC治疗反应和AA患者的生存率是否与 使用现有数据集的差异肿瘤生物学。 在本申请中，我们将利用两个独特的富含AA患者的OPC队列来检验假设 AA患者的OPC发展伴随着更积极的肿瘤生物学， 免疫抑制肿瘤免疫微环境（TIME）。在目标1中，我们将自我报告的种族与 计算出的与内在OPC肿瘤生物学和治疗反应相关的祖先。具体来说，我们将测试 肿瘤细胞多核化（侵袭性OPC生物学的特征，最近由我们的 多机构OPC队列研究）、生存率和AA OPC患者的差异基因表达 他们的非AA对应T分类，HPV状态和吸烟史。在目标2中，我们将自我- 既往未接受过治疗的AA患者中报告的人种和计算的祖先与时间和治疗反应变化的关系 OPC患者以及复发/转移性AA OPC患者中的免疫检查点抑制剂应答 疾病对于这两组分析，我们将部署新的，经过验证的机器学习方法来分析 传统的组织学载玻片，旨在促进跨多个其他机构的快速临床翻译。 完成拟议的研究将首次建立种族/血统、OPC 生物学行为和治疗反应。我们假设的成功验证将提供一个独特的 为AA OPC管理开发精确肿瘤学方法的机会，旨在逆转 这一未充分研究的患者人群在癌症特异性生存率方面的差异。