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

基本信息

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
项目类别：
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

项目摘要

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/Astract 胃癌（GC）是拉丁美洲裔癌症事件，死亡率和生存分布的主要原因，在加利福尼亚州乌卡特州和德克萨斯州。与非拉丁裔白人（NLW）相比，拉丁美洲人的GC发病率和死亡率高约2倍。实际上，在所有癌症类型中，GC是拉丁美洲裔差异最高的恶性肿瘤。拉丁裔与NLW女性相比，GC死亡率高2.6倍，而拉丁裔男性的风险高2.1倍。相对于NLW男性，被诊断为GC时死亡。尽管GC Burnen和大多数胃肿瘤带有“可药物”突变，仅批准了三种靶向疗法的GC。作为我们的一部分正在进行的UCAMP（加利福尼亚大学少数派患者的异种移植和试验）少数民族 - 聚焦PDTC，我们已经表明，拉丁美洲人的大多数GC分子亚型都携带可吸毒的突变，并且它们特别丰富了携带PI3K/AKT/MTOR多重和复杂基因组改变的肿瘤， 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具有突变和其他途径。因为约有35％的拉丁裔GC具有双/并发PI3K和CDK途径的变化，所以我们最初将使用这两种途径重点，但旨在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械数据，以帮助解决拉丁裔GC差异，这对于建立以少数族裔为中心的临床试验是必不可少的靶向疗法。作为我们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种患者来源的GC模型，其中约60％来自拉丁美洲人。我们还表明拉丁裔 PDX对PI3K抑制剂（PI3KI）和CDK抑制剂（CDKI）的双重处理有反应确定了具有对PIK3I Taselisib的独家响应的PIK3CA热点突变的模型。使用我们的加利福尼亚和德克萨斯州六个综合癌症中心的UCATS基础设施，我们在下一个周期的目标我们的U54研究是建立另外60个GC模型，全部来自少数群体，并以以下目的为目的： i）评估GC患者衍生的模型，以鉴定多个肿瘤中有效的药物组合途径变化； ii）了解PIK3CA突变肿瘤中对taselisib反应的机制； iii）评估遗传血统对化学疗法和拉丁裔靶向疗法的影响。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族裔 - 针对胃癌患者的临床试验。