权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defining the role of GNAS in gastrointestinal metastasis

定义 GNAS 在胃肠道转移中的作用

基本信息

批准号：
10644197
负责人：
Michael Foote
金额：
$ 26.88万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644197
关键词：
Adenylate Cyclase Advisory Committees Arginine Award Bioinformatics CRISPR/Cas technology Cancer Patient Carcinomatosis Cells Chemoresistance Clinical Trials DNA Data Development Development Plans Disseminated Malignant Neoplasm Down-Regulation Drug Targeting Educational workshop Epidemiology Exhibits Experimental Models Fingers Future GTP-Binding Protein alpha Subunits Gastrointestinal Neoplasms Gene Expression Genes Genomics Goals Greater sac of peritoneum Growth Guanosine Triphosphate Hydrolysis Impairment In Vitro International Investigation KRAS2 gene Knowledge Lung Neoplasms MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Memorial Sloan-Kettering Cancer Center Mentors Modeling Molecular Molecular Analysis Molecular Biology Molecular Conformation Molecular Profiling Morbidity - disease rate Mucinous Mucins Mus Mutate Mutation Neoplasm Metastasis Organoids PIK3CG gene Pancreas Pathogenicity Patients Pattern Peritoneal Phenotype Physicians Production RNA Recurrence Role Scientist Signal Pathway Signal Transduction TP53 gene Testing Therapeutic Therapeutic Effect Training Translational Research Tropism Tumor Suppressor Proteins Validation Xenograft procedure cancer type chemotherapy cohort drug development effective therapy experimental study gain of function gain of function mutation gastrointestinal gene regulatory network high risk improved in vivo inhibitor therapy innovation molecular phenotype mortality mouse model multiple omics mutant novel therapeutic intervention oncology service peritoneal cancer response targeted treatment translational physician treatment response treatment strategy tumor tumor DNA tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Patients with gastrointestinal (GI) metastases in the peritoneal cavity suffer high morbidity, chemotherapy resistance, and decreased overall survival. The molecular mechanism and phenotypic features that facilitate peritoneal metastasis are poorly understood, although mucin-expressing tumors exhibit especially high predilection for peritoneal spread. Preliminary analyses determined in a pan-cancer patient cohort that mucinous GI tumors are highly enriched in a specific mutation in GNAS that leads to pathogenic gain-of- function in the encoded G protein alpha subunit (GNAS). GNAS mutations are associated with pancreatic and small cell lung tumor development, yet the pathogenic mechanism mobilized by GNAS to facilitate metastasis is unknown. Preliminary data demonstrates that patients with GNAS-mutated GI cancers exhibit increased burden of peritoneal metastases, decreased response to first-line chemotherapy, and poor overall survival. Analysis of tumor DNA and RNA from independent groups of patient tumors shows that mutated GNAS may operate within a distinct gene-regulatory network that activates PI3K and MAPK signaling. The PI and collaborators established GNAS-mutated, patient-derived-organoids (PDOs) and a peritoneal metastasis mouse model to evaluate the hypothesis that GNAS is a key molecular driver that governs the signaling pathway involved in metastatic peritoneal seeding and growth. To test this hypothesis, the study will (1) define the GNAS-induced gene regulatory networks and phenotypic features that facilitate tumor progression in patient peritoneal metastasis and CRISPR-Cas9 gene- edited PDOs and (2) determine the impact of GNAS modulation on metastasis distribution and pathogenicity in vivo using xenograft metastatic models. Investigations will integrate multi-omic analyses with PDO experimental validation to improve the fundamental understanding of metastasis and validate GNAS signaling as a therapeutically-relevant target. The applicant, Dr. Michael Foote, is a rising Assistant Attending in the GI Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Foote has defined a 5-year plan to integrate his background in targeted drug development and computational bioinformatics with new expertise in experimental modeling and molecular biology. Dr. Foote will be mentored by a complementary advisory committee led by Dr. Luis Diaz, an international expert in genomics with a strong background in training successful independent physician scientists. Dr. Foote’s development plan includes supportive workshops and mentoring from an advisory committee of experts in molecular biology, cell signaling, and bioinformatics at MSKCC, a world-renowned translational center of excellence. Completion of the project goals will facilitate new therapeutic approaches for treating metastatic GI cancer and Dr. Foote’s development into an independent physician scientist and expert leader in GI metastasis.

项目总结/摘要腹膜腔中的胃肠道（GI）转移的患者具有高发病率，化疗耐药性和总生存率下降。分子机制和表型特征尽管表达粘蛋白肿瘤尤其表现出腹膜扩散的高倾向性。初步分析确定，在泛癌症患者队列中，粘液性胃肠道肿瘤在GNAS中的一种特异性突变中高度富集，这种突变导致致病性的在编码的G蛋白α亚基（GNAS）中起作用。GNAS突变与胰腺癌相关，小细胞肺肿瘤的发展，但致病机制动员GNAS，以促进转移不明初步数据表明，GNAS突变的GI癌患者表现出增加的腹膜转移负担、一线化疗反应降低和总生存率差。对来自独立患者肿瘤组的肿瘤DNA和RNA的分析表明，突变的GNAS可能在激活PI 3 K和MAPK信号传导的不同基因调控网络内运作。PI和合作者建立了GNAS突变的患者源性类器官（PDO）和腹膜转移小鼠模型，以评估GNAS是控制信号传导的关键分子驱动的假设参与转移性腹膜种植和生长的途径。为了验证这一假设，该研究将（1）定义GNAS诱导的基因调控网络，促进患者腹膜转移中肿瘤进展的表型特征和CRISPR-Cas9基因- 编辑的PDO和（2）确定GNAS调节对肿瘤转移分布和致病性的影响。体内使用异种移植转移模型。研究将多组学分析与PDO相结合实验验证，以提高对转移的基本理解并验证GNAS信号传导作为治疗相关的目标。申请人，迈克尔富特博士，是一个上升的助理出席在GI Memorial Sloan Kettering Cancer Center（MSKCC）富特博士制定了一个五年计划将他在靶向药物开发和计算生物信息学方面的背景与新的专业知识相结合，实验建模和分子生物学。富特博士将由一名辅助顾问指导该委员会由Luis迪亚兹博士领导，他是基因组学方面的国际专家，具有很强的培训背景成功的独立医生科学家。Foote博士的发展计划包括支持性研讨会，来自分子生物学、细胞信号传导和生物信息学专家咨询委员会的指导， MSKCC，世界知名的卓越翻译中心。项目目标的完成将促进新的治疗转移性胃肠道癌的治疗方法和Foote博士发展成为一个独立的胃肠道转移的内科医生、科学家和专家领导者。