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.

项目概要/摘要 腹膜腔胃肠道（GI）转移患者的发病率很高， 化疗耐药，并降低总体生存率的分子机制和表型特征。 尽管表达粘蛋白的肿瘤尤其表现出促进腹膜转移的机制，但人们对促进腹膜转移的机制知之甚少。 在泛癌患者队列中确定的腹膜扩散的高倾向性。 粘液性胃肠道肿瘤高度富含 GNAS 的特定突变，导致致病性增益 - 编码的 G 蛋白 α 亚基 (GNAS) 的功能突变与胰腺和胰腺相关。 小细胞肺肿瘤的发展，以及 GNAS 促进转移的致病机制 初步数据表明，患有 GNAS 突变的胃肠道癌症患者的发病率有所增加。 腹膜转移的负担、对一线化疗的反应降低以及总体生存率较差。 对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 PI3K 和 MAPK 信号传导的独特基因调控网络中发挥作用。 合作者建立了 GNAS 突变、患者来源的类器官 (PDO) 和腹膜转移 小鼠模型来评估 GNAS 是控制信号传导的关键分子驱动因素的假设 参与转移性腹膜种植和生长的途径。 为了检验这一假设，该研究将 (1) 定义 GNAS 诱导的基因调控网络和 促进患者腹膜转移肿瘤进展的表型特征和 CRISPR-Cas9 基因- 编辑 PDO 并 (2) 确定 GNAS 调节对转移分布和致病性的影响 使用异种移植转移模型进行体内研究将多组学分析与 PDO 结合起来。 实验验证以提高对转移的基本理解并验证 GNAS 信号传导 作为治疗相关目标，申请人 Michael Foote 博士是 GI 的一名晋升助理。 纪念斯隆凯特琳癌症中心 (MSKCC) 的肿瘤服务中心 Foote 博士制定了一个 5 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 Foote 博士将获得实验建模和分子生物学方面的补充顾问的指导。 由具有丰富培训背景的国际基因组学专家 Luis Diaz 博士领导的委员会 富特博士的发展计划包括支持性研讨会和成功的独立医师科学家。 由分子生物学、细胞信号传导和生物信息学专家组成的咨询委员会提供指导 MSKCC，世界著名的卓越转化中心，项目目标的完成将促进新的成果。 治疗转移性胃肠道癌症的治疗方法以及 Foote 博士发展成为独立的 胃肠道转移领域的医师科学家和专家领导者。