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

通过患者衍生模型推进拉丁裔胃癌精准医学

• 批准号: 10733395
• 负责人: Luis Guillermo Carvajal Carmona
• 金额: $ 31.79万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733395
• 关键词: Address; African American; Biological Assay; California; Cancer Burden; Cancer Etiology; Cancer Model; Cancer Patient; Cancer Therapy Evaluation Program; Cell Cycle; Chemotherapy-Oncologic Procedure; Clinical Research; Clinical Trials; Collection; Complex; Comprehensive Cancer Center; Data; Development; Diagnosis; Disparity; Drug Combinations; Drug Modelings; Ethnic Origin; Ethnic Population; European; FDA approved; FRAP1 gene; Frequencies; Funding; Generations; Genes; Genetic; Genome; Genomics; Goals; High Prevalence; In Vitro; Incidence; Indigenous American; Infrastructure; Knowledge; Latina Population; Latino; Latino Population; Lung Neoplasms; Malignant Neoplasms; Medicine; Minority; Minority Groups; Modeling; Molecular Target; Mutate; Mutation; Organoids; PI3K/AKT; PIK3CA gene; PIK3CG gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphotransferases; Population; Race; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Resistance; Signal Pathway; Somatic Mutation; Stomach Neoplasms; Testing; Texas; The Cancer Genome Atlas; Translating; Translational Research; Universities; Woman; Work; cancer genome; cancer genomics; cancer health disparity; cancer therapy; cancer type; candidate identification; candidate marker; chemotherapy; ethnic minority; exome sequencing; genomic data; high risk; in vivo; inhibitor; kinase inhibitor; male; malignant stomach neoplasm; men; minority patient; molecular subtypes; mortality; mortality disparity; mutant; novel drug combination; novel therapeutics; patient derived xenograft model; pre-clinical; precision medicine; precision oncology; racial minority; racial population; repository; response; survival disparity; targeted cancer therapy; targeted therapy trials; targeted treatment; treatment response; tumor; tumor growth

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.

项目摘要/摘要 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族裔以及 UCaTS 加利福尼亚州和 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约 2 倍。 事实上，在所有癌症类型中，胃癌是拉丁裔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，而拉丁裔男性的 GC 死亡率高 2.1 倍 与 NLW 男性相比，诊断为 GC 时死亡。尽管 GC 负担很高，而且大多数胃 肿瘤携带“可药物”突变，只有三种靶向疗法已被批准用于GC。作为我们的一部分 正在进行的 UCaMP（加州大学少数族裔患者衍生异种移植物开发和试验）少数- 以 PDTC 为重点，我们已经证明拉丁美洲人的大多数 GC 分子亚型都携带可药物突变，并且 它们在 PI3K/AKT/mTOR 中携带多种复杂基因组改变的肿瘤中特别丰富， CDK、WNT 和 RTK/RAS 通路基因。超过一半的拉丁裔肿瘤在这些区域的多个基因中存在突变 和其他途径。因为约 35% 的拉丁裔 GC 具有双重/并发 PI3K 和 CDK 通路改变，我们 我们最初将集中使用这两种途径进行研究，但目标是扩展到其他类型的肿瘤 突变的途径。该项目旨在开发一系列临床前和机制数据，以帮助解决 拉丁裔 GC 差异，这对于建立以少数族裔为重点的临床试验是必要的 靶向治疗。作为 NCI 资助的 UCaMP PDTC 的一部分，我们的 UCaTS 研究团队已经成功 创建了 55 个源自患者的 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) 的双重治疗有反应，并且具有 确定了一个具有 PIK3CA 热点突变的模型，该模型对 PIK3i taselisib 具有精致的反应。使用我们的 加州和德克萨斯州六个综合癌症中心的 UCaTS 基础设施，我们下一个周期的目标 我们的 U54 研究是建立另外 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 患者衍生模型，以识别具有多种疾病的肿瘤中的有效药物组合 途径改变； ii) 了解 PIK3CA 突变肿瘤中 taselisib 的反应机制； iii) 评估拉丁裔遗传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，可以快速转化为少数群体- 重点针对胃癌患者进行临床试验。