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

项目概要/ASTRACT 胃癌（GC）是拉丁美洲人癌症发病率、死亡率和生存差异的主要原因， 最大和最年轻的美国少数民族和最大的种族/族裔群体在UCaTS州的加州和 德克萨斯与非拉丁裔白人（NLW）相比，拉丁裔的GC发病率和死亡率高2倍。 事实上，在所有癌症类型中，GC是拉丁美洲人中差异率最高的恶性肿瘤。拉丁裔 与NLW女性相比，GC死亡率高2.6倍，而拉丁裔男性为2.1倍。风险增加一倍 与NLW男性相比，当被诊断为GC时死亡。尽管如此高的GC负担和事实， 尽管肿瘤携带“可药物化”的突变，但只有三种靶向疗法被批准用于GC。作为我们 正在进行的UCaMP（加州大学少数族裔患者衍生异种移植物开发和试验）少数族裔- 聚焦PDTC，我们已经表明，拉丁美洲人中的大多数GC分子亚型携带可药用突变， 它们特别富集于携带PI 3 K/AKT/mTOR的多重和复杂基因组改变的肿瘤中， CDK、WNT和RTK/RAS途径基因。超过一半的拉丁美洲肿瘤在这些基因中有多个基因突变。 和其他途径。由于约35%的拉丁裔GC具有双重/并发PI 3 K和CDK通路改变，我们 我们的研究最初将集中在这两种途径上，但我们的目标是扩展到其他类型的肿瘤， 变异的路径该项目旨在开发一系列临床前和机械数据，以帮助解决 拉丁裔GC的差异，这将是必要的，为建立少数民族为重点的临床试验， 靶向治疗。作为我们的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个患者来源的GC模型，其中约60%的模型来自拉丁美洲人。我们还发现，拉丁美洲人 PDX对PI 3 K抑制剂（PI 3 Ki）和CDK抑制剂（CDKi）的双重治疗有反应， 鉴定了具有PIK 3CA热点突变的模型，该模型对PIK 3 i taselisib具有精细响应。使用我们 UCaTS在加州和得克萨斯州的六个综合癌症中心的基础设施，我们在下一个周期的目标， 我们的U 54研究是建立额外的60个GC模型，全部来自少数民族，并致力于以下目标： i）评估GC患者来源的模型，用于鉴定具有多种肿瘤的肿瘤中的有效药物组合。 ii）了解PIK 3CA突变肿瘤中对他塞利昔布的应答机制; iii）评估遗传血统对拉丁美洲人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民族- 针对胃癌患者的临床试验。

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.