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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.

项目总结/文摘