Advancing gastric cancer precision medicine in Latinos through patient-derived modeling

项目摘要/项目摘要 在拉美裔美国人中，胃癌是癌症发病率、死亡率和生存差距的主要原因。 美国最大和最年轻的少数民族，以及加州和加州大学洛杉矶分校最大的种族/民族群体 德克萨斯州。与非拉丁裔白人(NLW)相比，拉丁裔的GC发病率和死亡率高出~&gt；2倍。 事实上，在所有癌症类型中，GC是拉丁裔中差异比例最高的恶性肿瘤。拉丁语 与NLW女性相比，GC死亡率是NLW女性的2.6倍，而拉丁裔男性患癌症的风险是NLW女性的2.1倍 与NLW男性相比，被诊断为GC时死亡。尽管GC负担很高，而且大多数胃部 虽然肿瘤携带“可药物”突变，但只有三种靶向治疗被批准用于GC。作为我们的一部分 正在进行的UCaMP(加州大学少数民族患者衍生的异种移植开发和试验)少数民族- 聚焦于PDTC，我们已经表明在拉丁裔中大多数GC分子亚型携带可药物突变，并且 它们在携带PI3K/AKT/mTOR多个复杂基因组改变的肿瘤中尤其丰富， CDK、WNT和RTK/RAS途径基因。超过一半的拉丁裔肿瘤在这些基因中有多个基因突变 和其他路径。由于约35%的拉丁裔GC具有双重/并发的PI3K和CDK途径改变，我们 最初我们将重点研究这两种途径，但将致力于扩展到其他类型的肿瘤与联合- 突变的路径。该项目旨在开发一系列临床前和机械性数据，将有助于解决 拉丁裔GC差异，这将是建立以少数族裔为重点的临床试验所必需的 有针对性的治疗。作为NCI资助的UCAMP PDTC的一部分，我们的UCATS研究团队已经成功地 创建了55个患者衍生的GC模型，其中约60%的模型来自拉丁裔。我们还表明，拉丁裔 PDX对PI3K抑制剂(PI3KI)和CDK抑制剂(CDKI)双重治疗有反应，并有 确定了一个带有PIK3CA热点突变的模型，该模型对PIK3i taselisib有精妙的反应。使用我们的 加州和德克萨斯州的六个综合性癌症中心的UCATS基础设施，我们在下一个周期的目标是 我们的U54研究将建立另外60个GC模型，全部来自少数族裔，并致力于以下目标： I)评估GC患者衍生的模型，以确定有效的药物组合治疗多发性肿瘤 途径改变；ii)了解PIK3CA突变型肿瘤对他赛昔布的反应机制； 三)评估拉美裔人的基因血统对化疗和靶向治疗的影响。 通过这些研究，我们将开发有效的药物组合，可以迅速转化为少数药物- 针对胃癌患者的重点临床试验。

PROJECT SUMMARY/ASTRACT Gastric cancer (GC) is a leading cause of cancer incidence, mortality, and survival disparities in Latinos, the largest and youngest U.S. minority and the largest racial/ethnic group in the UCaTS states of California and Texas. When compared to non-Latino whites (NLW), GC incidence and mortality is ~>2-fold higher in Latinos. Indeed, among all cancer types, GC is the malignancy with the highest disparity ratio among Latinos. Latinas have a 2.6-fold higher GC mortality compared to NLW women, while Latino men are at a 2.1.-fold higher risk of dying when diagnosed with GC relative to NLW men. Despite this high GC burden and the fact that most gastric tumors carry “druggable” mutations, only three targeted therapies have been approved for GC. As part of our ongoing UCaMP (University of California Minority Patient-Derived Xenograft Development and Trial) minority- focused PDTC, we have shown that most GC molecular subtypes in Latinos carry druggable mutations and that they are particularly enriched in tumors carrying multiple and complex genome alterations in PI3K/AKT/mTOR, CDK, WNT, and RTK/RAS pathway genes. Over half of Latino tumors have mutations in multiple genes in these and other pathways. Because ~35% of Latino GCs have dual/concurrent PI3K and CDK pathway alterations, we will initially focus our studies using these two pathways but will aim to expand to other type of tumors with co- mutated pathways. This project aims to develop a body of pre-clinical and mechanistic data that will help address Latino GC disparities, and that will be necessary for the establishment of minority-focused clinical trials of targeted therapies. As part of our NCI-funded UCaMP PDTC, our UCaTS research team has already successfully created 55 patient-derived GC models, with ~60% of the models from Latinos. We have also shown that Latino PDXs are responsive to dual treatments with PI3K inhibitors (PI3Ki) and CDK inhibitors (CDKi) and have identified a model with PIK3CA hotspot mutations with an exquisite response to the PIK3i taselisib. Using our UCaTS infrastructure of six comprehensive cancer centers in California and Texas, our goal in the next cycle of our U54 study is to establish an additional 60 GC models, all from minorities, and to work on the following aims: i) To evaluate GC patient-derived models for identifying efficacious drug combination in tumors with multiple pathway alterations; ii) To understand the mechanisms of response to taselisib in PIK3CA mutant tumors and; iii) To evaluate the effect of genetic ancestry in response to chemotherapies and targeted therapies in Latinos. Through these studies we will develop effective drug combinations that can be rapidly translated into minority- focused clinical trials for gastric cancer patients.