Functional characterization of novel oncogenic loci driving progression and immune response in gastrointestinal cancer

驱动胃肠癌进展和免疫反应的新型致癌位点的功能特征

基本信息

批准号：
10283386
负责人：
Yuan-Hung Lo
金额：
$ 17.17万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10283386
关键词：
3-Dimensional ARID1A gene Air Anatomy Automobile Driving Biological Biology CRISPR interference CRISPR/Cas technology Cancer Patient Candidate Disease Gene Cells Chromosomal Instability Coculture Techniques Coupled Cytotoxic Chemotherapy Data Detection Disease Ecosystem Engineering Epithelial Event Evolution Exhibits Experimental Models Gene Expression Generations Genes Genetic Genetic Engineering Genome Stability Genomic approach Genomics Genotype Goals Human Human Herpesvirus 4 Immune Immune Evasion Immune response Immune system Immunology Immunooncology Immunotherapeutic agent Immunotherapy In Vitro Inflammatory Liquid substance MLH1 gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Measures Mediating Mentors Methodology Methods Microsatellite Instability Modeling Molecular Monitor Mutate Mutation Natural Immunity Natural Killer Cells Normal tissue morphology Oncogenes Oncogenic Oncology Organoids Patients Pharmacology Phase Phenotype Physiological Population Predisposition Proteins Reaction Regulation Research Research Personnel Resistance Resistance development Role Series Shapes Somatic Mutation System T-Lymphocyte TP53 gene Technology Testing The Cancer Genome Atlas Therapeutic Training Tumor Immunity Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Work Xenograft procedure adaptive immunity base cancer cell cancer immunotherapy cancer subtypes cancer surgery cancer therapy career cell killing conventional therapy gastric organoids gastric tumorigenesis genetic approach genetic manipulation genome editing immune checkpoint blockade improved in vitro Model in vivo insight malignant stomach neoplasm mouse model multimodality mutant neoantigens neoplasm immunotherapy neoplastic cell next generation novel novel therapeutics patient subsets preservation response skills success tool treatment response tumor tumor immunology tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Gastric cancer (GC) is one of the most common and lethal cancers worldwide. GC surgery is highly morbid, and responses to the limited array of treatment options are poor. There is hope that recent genomic sequencing data can be leveraged to develop newer, improved molecular therapies for GC, but rigorous mechanistic testing is still needed to validate the therapeutic potential of targeting any newly proposed oncogenes. Immunotherapy is an exciting new therapy that has revolutionized oncology and shows tremendous potential. In contrast to cytotoxic chemotherapies, which exhibit fractional killing invariably leading to resistance, immune cells can infiltrate almost all anatomic sites to recognize and completely eliminate malignant cells in primary and wide-spread metastatic disease. However, the immune system’s full anti-tumor killing potential can be restricted by evasive measures by the tumor and/or intrinsic immunosuppressive mechanisms that limit collateral damage to normal tissues during anti-tumor inflammatory reactions. In GC, little is known about how cancer cells evade the system, and studies investigating the molecular mechanisms underlying tumor- immune interactions have been limited by a lack of physiologically relevant in vitro human systems where state-of-the-art genetic approaches can be applied. These mechanisms are important because they would be essential to our understanding of GC tumorigenesis and the regulation of immunotherapeutic responses. Such mechanistic insight on the immune system to GC is fundamental and significant to advance and improve GC therapies. In this proposal, we utilize a series of CRISPR/Cas9 genome editing tools to create novel forward genetically engineered models of the four major GC subtypes as defined by The Cancer Genome Atlas project, including chromosomal instability (CIN), genomic stability (GS), microsatellite instability (MSI) and Epstein-Barr virus-associated (EBV) in primary 3D human gastric organoids (Aim1 and Aim2). In a parallel translational aim, we propose to use a second-generation patient-derived organoid model that allows tumor and stroma to be preserved alongside each other to study interactions between tumor cells and their veritable ecosystem of cohabiting immune cells in primary human gastric cancer (Aim 3). The overall goal of this project is to investigate how genetic alterations contribute to gastric tumorigenesis and immunotherapeutic responses using synergistic next-generation in vivo and in vitro models. Collectively, the results of this project will provide new insights into fundamental aspects of the molecular mechanisms underlying the tumor-immune interaction and enhance current GC immunotherapies. A team of expert mentors, advisors and collaborators will train Dr. Lo in new methods that are critical to the success of this research. The combination of mentoring support, skills, and data obtained in the K99 phase will provide Dr. Lo a springboard to achieving independence as an investigator in the R00 phase and beyond.

项目概要/摘要胃癌 (GC) 是世界上最常见和致命的癌症之一，GC 手术的发病率很高。对有限的治疗方案的反应很差，最近的基因组测序有希望。数据可用于开发更新、改进的 GC 分子疗法，但需要严格的机械测试仍然需要验证针对任何新提出的癌基因的治疗潜力。免疫疗法是一种令人兴奋的新疗法，它彻底改变了肿瘤学并显示出巨大的潜力与细胞毒性化疗相反，细胞毒性化疗总是会导致耐药性。免疫细胞可以渗透到几乎所有的解剖部位，识别并彻底消灭体内的恶性细胞。然而，免疫系统的全部抗肿瘤杀伤潜力可以。受到肿瘤和/或内在免疫抑制机制的规避措施的限制 GC 中抗肿瘤炎症反应对正常组织造成的附带损害目前尚不清楚。癌细胞逃避该系统，并研究了肿瘤背后的分子机制由于缺乏生理相关的体外人体系统，免疫相互作用受到限制可以应用最先进的遗传方法的地方，这些机制很重要，因为它们。对于我们理解 GC 肿瘤发生和免疫治疗的调节至关重要这种对免疫系统对 GC 反应的机制了解对于推进免疫系统的反应具有基础性和重要意义。并改进 GC 疗法。在该提案中，我们利用一系列 CRISPR/Cas9 基因组编辑工具来创建。癌症基因组定义的四种主要 GC 亚型的新型正向基因工程模型 Atlas项目，包括染色体不稳定性（CIN）、基因组稳定性（GS）、微卫星不稳定性（MSI）和原代 3D 人胃类器官（Aim1 和 Aim2）中的 Epstein-Barr 病毒相关 (EBV)。为了转化目标，我们建议使用第二代患者衍生的类器官模型，该模型允许肿瘤和基质彼此并排保存，以研究肿瘤细胞与其真实细胞之间的相互作用原发性人类胃癌中共居免疫细胞的生态系统（目标 3）。旨在研究基因改变如何促进胃肿瘤发生和免疫治疗反应总的来说，该项目的结果将提供协同的下一代体内和体外模型。对肿瘤-免疫相互作用分子机制基本方面的新见解并增强目前的GC免疫疗法。由专家导师、顾问和合作者组成的团队将用新方法对卢博士进行培训，这些方法对于这项研究的成功结合了 K99 阶段获得的指导支持、技能和数据。将为 Lo 博士提供一个跳板，使他能够在 R00 阶段及以后获得独立的研究者身份。