Defining the role of GNAS in gastrointestinal metastasis

定义 GNAS 在胃肠道转移中的作用

• 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
• 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

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.

项目摘要/摘要 腹膜腔中胃肠道转移（GI）转移的患者的发病率高， 化学疗法抗性，并提高了总体生存率。分子机制和表型特征 促进腹膜转移的促进的理解很少，尽管表达粘蛋白的肿瘤尤其表现出 腹膜扩散的高预测。在Pan-Cancer患者队列中确定的初步分析 粘液胃肠道肿瘤高度富集在GNA中的特异性突变中，从而导致致病性获得 编码G蛋白α亚基（GNA）中的功能。 GNA突变与胰腺和 小细胞肺肿瘤发育，但是GNA动员的致病机制促进转移 是未知的。初步数据表明，暴露于GNA突变的GI癌症患者增加 腹膜转移的负担，对一线化学疗法的反应减少，总生存率差。 对患者肿瘤的独立组的肿瘤DNA和RNA的分析表明，突变的GNA可能 在激活PI3K和MAPK信号传导的不同基因调节网络中运行。 pi和 合作者建立了GNA突破的，患者衍生的甲醇（PDOS）和腹膜转移 鼠标模型评估GNA是控制信号的关键分子驱动器的假设 涉及转移性腹膜播种和生长的途径。 为了检验该假设，该研究将（1）定义GNA诱导的基因调节网络和 促进患者腹膜转移和CRISPR-CAS9基因的肿瘤进展的表型特征 编辑的PDOS和（2）确定GNA调制对转移分布和致病性的影响 使用特种志转移模型的体内。调查将与PDO相结合 实验验证以提高对转移和验证GNA信号的基本理解的基本理解 作为与治疗相关的目标。申请人迈克尔·富特（Michael Foote）博士是参加GI的助手 纪念斯隆·凯特林癌症中心（MSKCC）的肿瘤学服务。 Foote博士定义了5年计划 将他在有针对性的药物开发和计算生物信息学方面的背景与新专业知识相结合 在实验建模和分子生物学中。 Foote博士将由完整的咨询 由培训方面强大背景的国际基因组学专家路易斯·迪亚兹（Luis Diaz）领导的委员会 成功的独立物理科学家。 Foote博士的发展计划包括支持研讨会和 来自分子生物学，细胞信号和生物信息学专家咨询委员会的指导 MSKCC，世界知名的转化卓越中心。项目目标的完成将有助于新的 治疗转移性胃肠道癌和Foote Dravent的治疗方法 GI转移的医师科学家和专家领导者。