Research Project 1 PDAC Molecular Subtypes Contribute to Cancer Health Disparities

研究项目 1 PDAC 分子亚型导致癌症健康差异

• 批准号: 10733314
• 负责人: Nicholas Taylor Woods
• 金额: $ 23.47万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733314
• 关键词: Back; Benchmarking; Biological Assay; Black Populations; Black race; Cachexia; Cells; Characteristics; Chemoresistance; Chromatin; Classification; Clinical; Clinical Management; Data; Development; Disease; Disparity; EZH2 gene; Early Therapeutic-Clinical Trials Network; Epigenetic Process; Ethnic Origin; Exhibits; Face; Genetic Transcription; Goals; Hispanic Populations; Incidence; Inflammatory; Knock-out; Latino; Libraries; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mass Spectrum Analysis; Metabolic; Methods; Modeling; Molecular; Multivariate Analysis; Organoids; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Polycomb; Population Heterogeneity; Precision therapeutics; Prediction of Response to Therapy; Proteins; Proteome; Proteomics; RNA; Race; Refractory; Regulation; Repression; Repressor Proteins; Research; Research Project Grants; Resistance; Role; S-Phase Fraction; Socioeconomic Status; Specific qualifier value; System; Therapeutic; Treatment outcome; Tumor stage; Work; black patient; cancer health disparity; chemotherapy; clinically relevant; cohort; design; epigenetic silencing; ethnic diversity; ethnic health disparity; experience; gene repression; genetic manipulation; health disparity; health equity; improved; mRNA Expression; malignant breast neoplasm; model building; molecular marker; molecular subtypes; multiple omics; mutant; new therapeutic target; pancreatic tumorigenesis; patient derived xenograft model; patient response; progenitor; programs; promoter; proteomic signature; racial diversity; racial health disparity; racial population; recruit; response; socioeconomics; statistics; transcriptome sequencing; treatment response; treatment strategy; tumor; ubiquitin ligase

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to current treatment strategies due in part to adaptive mechanisms of chemoresistance. Racial health disparities also confound the treatment and care of these patients. Blacks have significantly higher incidence rates of PDAC and decreased survival times compared to Whites and Latino/Hispanics (L/H) even after socioeconomic status and tumor stages are controlled. Therefore, it is likely different racial groups exhibit unique molecular characteristics in PDAC tumors that contribute to these health disparities. The molecular characteristics that distinguish PDAC tumors between racial groups have the potential to identify novel therapeutic targets required to overcome the disparities. Indeed, delineating the underlying molecular basis for health disparities in lung, breast and prostate cancers has led to therapeutic advancements and improved patient outcomes. Similar breakthroughs for PDAC are possible and needed for this deadly disease, but this field of research has not yet been adequately explored. We identified 4 distinct subtypes of PDAC (Metabolic, Progenitor-like, Proliferative, and Inflammatory) that can be distinguished using multivariate analysis of quantitative mass spectrometry data. These PDAC subtypes are predictive of therapeutic response, but this has not yet been analyzed in a racially diverse population. We have examined the proteomes of primary PDAC tumors using quantitative mass spectrometry and identified unique protein signatures for Blacks, L/H, and Whites. In PDAC tumors from Black patients, we observed features consistent with the Inflammatory subtype of PDAC, which is characterized by an inflammatory microenvironment and resistance to chemotherapy. Therefore, it is possible that race influences subtype and Blacks could preferentially develop the more aggressive and treatment refractory Inflammatory subtype. Therefore, strategies are needed to modulate subtype to improve response to chemotherapy. Toward this goal, our proteomic analysis also identified that the polycomb repressor complex 1 protein RNF2 is upregulated in PDACs from Blacks compared to Whites. We have also discovered that RNF2 regulates mRNA expression of the PDAC subtype specification factor GATA6 and inhibiting RNF2 promotes a molecular shift toward the more chemosensitive Classical subtype of PDAC. In general terms, the Specific Aims in this proposal are designed to: 1) Determine the interaction between race and PDAC subtype development in PDX models; 2) Determine the impact of RNF2 on EZH2 regulation of GATA6 and in diverse PDAC PDX models; and 3) To quantify the response of PDAC PDX to select NCI-IND compounds targeting epigenetic modifiers. The successful completion of these aims has the potential to mitigate racial health disparities in PDAC and broadly improve overall patient survival by optimizing precision therapeutic strategies.

项目概要 胰腺导管腺癌（PDAC）是一种致命疾病，目前的治疗策略难以治愈 部分原因是化学耐药性的适应性机制。种族健康差异也使治疗变得混乱 以及对这些患者的护理。黑人的 PDAC 发病率明显较高，且生存率较低 与白人和拉丁裔/西班牙裔 (L/H) 相比，即使社会经济状况和肿瘤分期已确定 受控。因此，不同种族群体在 PDAC 肿瘤中可能表现出独特的分子特征 造成这些健康差异的因素。区分 PDAC 肿瘤的分子特征 种族群体有潜力确定克服差异所需的新治疗目标。的确， 描述肺癌、乳腺癌和前列腺癌健康差异的潜在分子基础已导致 治疗的进步和患者治疗效果的改善。 PDAC 也可能取得类似的突破 这种致命疾病所需的药物，但这一研究领域尚未得到充分探索。我们确定了 4 可区分的不同 PDAC 亚型（代谢型、祖细胞型、增殖型和炎症型） 使用定量质谱数据的多变量分析。这些 PDAC 亚型可预测 治疗反应，但这尚未在不同种族的人群中进行分析。我们已经检查了 使用定量质谱分析原发性 PDAC 肿瘤的蛋白质组并鉴定出独特的蛋白质 黑人、左翼/右翼和白人的签名。在黑人患者的 PDAC 肿瘤中，我们观察到一致的特征 PDAC 的炎症亚型，其特征是炎症微环境和 对化疗的抵抗力。因此，种族可能会影响亚型，黑人可以优先选择 开发更具侵袭性和难治性的炎症亚型。因此需要策略 调节亚型以改善对化疗的反应。为了实现这一目标，我们的蛋白质组分析还 发现与黑人相比，多梳阻遏复合物 1 蛋白 RNF2 在黑人 PDAC 中表达上调 给白人。我们还发现 RNF2 调节 PDAC 亚型规范的 mRNA 表达 GATA6 因子和抑制 RNF2 促进分子向化学敏感性更高的经典亚型转变 的 PDAC。一般而言，本提案中的具体目标旨在： 1) 确定交互 PDX 模型中种族和 PDAC 亚型开发之间的关系； 2) 确定RNF2对EZH2的影响 GATA6 和多种 PDAC PDX 模型的调节； 3) 量化 PDAC PDX 的响应以选择 针对表观遗传修饰剂的 NCI-IND 化合物。成功完成这些目标有潜力 通过优化精确度来减轻 PDAC 中的种族健康差异并广泛提高患者的总体生存率 治疗策略。