Research Project 1 PDAC Molecular Subtypes Contribute to Cancer Health Disparities

项目总结 摘要胰腺导管腺癌(Pdac)是一种致命的疾病，目前的治疗方法难以奏效。 部分原因是化疗耐药的适应性机制。种族健康差异也扰乱了治疗 以及对这些病人的照顾。黑人的PDAC发病率明显较高，存活率较低 与白人和拉丁裔/拉美裔(L/H)相比，即使在社会经济地位和肿瘤分期之后也是如此 控制住了。因此，可能不同的种族群体在PDAC肿瘤中表现出独特的分子特征。 造成这些健康差距的因素。区分PDAC肿瘤的分子特征 种族群体有可能确定克服差异所需的新的治疗目标。的确， 描绘肺癌、乳腺癌和前列腺癌健康差异的潜在分子基础导致了 治疗的进步和患者结果的改善。PDAC的类似突破也是可能的，并且 这种致命疾病所需的药物，但这一领域的研究尚未得到充分探索。我们确定了4个 可区分的不同的PDAC亚型(代谢性、祖细胞样、增生性和炎症性) 采用多元分析方法对定量质谱学数据进行分析。这些PDAC子类型可预测 治疗反应，但这还没有在种族多样化的人群中进行分析。我们已经研究了 定量质谱法分析原发性PDAC肿瘤的蛋白质组并鉴定其特有蛋白质 黑人、L/H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 炎症性PDAC亚型，以炎性微环境和 对化疗有抵抗力。因此，种族可能影响亚型，黑人可能优先 发展更具侵袭性和治疗难治性的炎症性亚型。因此，战略是必要的。 调整亚型，提高化疗疗效。为了实现这一目标，我们的蛋白质组分析也 经比较发现，多梳抑制物复合体1蛋白RNF2在黑人的PDAC中上调 敬怀特人。我们还发现RNF2调节PDAC亚型规范的mRNA表达 因子GATA6和抑制RNF2促进分子向化疗敏感性更高的经典亚型转变 PDAC的性能。总的来说，本提案中的具体目标旨在：1)确定互动 PDX模型中RACE和PDAC亚型发展之间的关系；2)确定RNF2对EZH2的影响 GATA6和在不同的PDAC PDX模型中的调节；以及3)量化PDAC PDX的响应以选择 NCI-Ind化合物靶向表观遗传修饰物。这些目标的成功实现具有潜力 通过优化精确度来缓解PDAC中的种族健康差异，并广泛提高总体患者存活率 治疗策略。

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.