Investigating the Role of KEAP1 Germline and Somatic Mutations in Renal Cell Carcinoma

研究 KEAP1 种系和体细胞突变在肾细胞癌中的作用

• 批准号: 10740481
• 负责人: Maria Carlo
• 金额: $ 25.9万
• 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: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740481
• 关键词: Address; Advisory Committees; Affect; Aggressive Clinical Course; Alleles; Antioxidants; Appointment; Award; Bioinformatics; Biological Models; Cancer Model; Cancer-Predisposing Gene; Cell Line; Clear cell renal cell carcinoma; Clinical; Collaborations; Core Facility; Cysteine; Development; Development Plans; Drug Targeting; Early identification; Ensure; Family; Fumarate Hydratase; Fumarate Hydratase Deficiency; Fumarates; Funding; Future; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Genetic Services; Genitourinary system; Genomics; Germ-Line Mutation; Glutathione; Goals; Hereditary Renal Cell Carcinoma; Heritability; Histologic; Histology; Human Resources; Immunohistochemistry; In Vitro; Individual; Inherited; Institution; Laboratories; Lead; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Medical Genetics; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolic Pathway; Methodology; Molecular; Mutate; Mutation; Neurofibromin 2; Oncogenic; Oncology; Organoids; Pathologic; Pathway interactions; Patients; Phenotype; Positioning Attribute; Predisposition; Process; Prognosis; Renal Cell Carcinoma; Renal carcinoma; Research; Research Personnel; Resources; Risk; Risk Reduction; Role; Running; Scientist; Screening for cancer; Somatic Mutation; Susceptibility Gene; Syndrome; Techniques; Testing; Training; Translational Research; Tumor Suppressor Genes; United States; Up-Regulation; Variant; Work; cancer predisposition; cancer prevention; cancer therapy; career development; cell growth; cohort; experimental study; functional genomics; genetic epidemiology; genomic profiles; improved; in vivo; interest; loss of function; metabolomics; nephrogenesis; new therapeutic target; novel; patient derived xenograft model; patient subsets; predictive tools; response; screening; skills; targeted exome sequencing; targeted treatment; transcriptomics; translational model; tumor; tumorigenesis

PROJECT SUMMARY Candidate: Maria I. Carlo, MD is an Assistant Attending in Medicine at Memorial Sloan Kettering Cancer Center (MSK) with a dual appointment in the Genitourinary Oncology and Clinical Genetics services. Dr. Carlo's clinical and research interests are in hereditary RCC, a cancer that has a poor prognosis when identified in advanced stages. Under the mentorship of Kenneth Offit, MD, MPH and Ari Hakimi, MD she has begun work to elucidate the role of KEAP1 in the susceptibility to RCC and to define the phenotype of RCCs with KEAP1 mutations. Dr. Carlo's goal is to develop an independent laboratory to do translational work in the genetic predisposition to RCC and its implication for cancer screening and targeted treatment. Career Development Plan: Drs. Carlo, Offit, and Hakimi have developed a plan to ensure that Dr. Carlo has the necessary training, mentorship, and support to effectively transition to an independent researcher who can successfully lead genomic discovery studies in RCC. This plan entails formal courses in genetic epidemiology, bioinformatics, and cancer modeling, informal collaborations with scientists from MSK laboratories, and training with personnel from MSK core facilities. Dr. Carlo has organized an Advisory Committee with expertise relevant to her proposal, and they will guide her in successfully completing the goals of her proposed research. Dr. Offit and the Advisory Committee will also guide Dr. Carlo to ensure progress in the promotion process and garnering independent research funding towards the end of the K08 award period. Research Plan: Despite several known genetic RCC syndromes, the majority of familial RCC remains unexplained. The proposed project will use a large cohort of 928 patients with RCC who have undergone parallel tumor and germline targeted exome sequencing. In a subgroup of patients with RCC of unclassified histology, germline and somatic predicted loss-of-function variants were identified in KEAP1, which encodes a negative regulator of NRF2, the key activator of the antioxidant response pathway. These tumors are histologically similar to Fumarate Hydratase (FH)-deficient RCCs, which arise from germline mutations in the FH gene. Loss of function of FH or KEAP1 can activate the NRF2 pathway. Dr. Carlo hypothesizes that, similar to FH, KEAP1 loss-of-function germline variants increase risk of RCC, and mutations in KEAP1 contribute to the development of RCC in an NRF2-dependent manner. Dr. Carlo aims to (1) characterize KEAP1-mutated RCC using genomic, transcriptomic and metabolic techniques, and (2) delineate the effects of KEAP1 and FH mutations on malignant transformation in RCC model systems. The overarching goal is to elucidate the role and implications of germline and somatic KEAP1 mutations in RCC to direct cancer screening and develop rational targeted therapies.

项目概要 候选人：Maria I. Carlo，医学博士是纪念斯隆凯特琳癌症中心的医学助理 中心 (MSK) 在泌尿生殖肿瘤学和临床遗传学服务方面拥有双重任命。博士。 卡罗的临床和研究兴趣是遗传性肾细胞癌，这是一种预后不良的癌症 在高级阶段确定。在 Kenneth Offit（医学博士、公共卫生硕士）和 Ari Hakimi（医学博士）的指导下，她 开始致力于阐明 KEAP1 在 RCC 易感性中的作用并定义 RCC 的表型 具有 KEAP1 突变。卡罗博士的目标是建立一个独立的实验室来进行转化工作 RCC 的遗传易感性及其对癌症筛查和靶向治疗的影响。 职业发展计划：博士。卡洛、奥菲特和哈基米制定了一项计划，以确保卡洛博士 必要的培训、指导和支持，以有效地转变为能够 成功领导 RCC 基因组发现研究。该计划需要遗传流行病学的正式课程， 生物信息学和癌症建模、与 MSK 斯隆实验室科学家的非正式合作以及培训 与 MSK 斯隆核心设施的人员一起。卡洛博士组织了一个具有专业知识的咨询委员会 与她的提案相关，他们将指导她成功完成她拟议的研究目标。 Offit博士和咨询委员会还将指导Carlo博士确保晋升过程中取得进展以及 在 K08 奖励期结束时获得独立研究经费。 研究计划：尽管有几种已知的遗传性 RCC 综合征，但大多数家族性 RCC 仍然是 无法解释。拟议的项目将使用一个由 928 名接受过 RCC 治疗的患者组成的大型队列。 并行肿瘤和种系靶向外显子组测序。在未分类的 RCC 患者亚组中 KEAP1 中鉴定出了组织学、种系和体细胞预测的功能丧失变异，该变异编码 NRF2 的负调节因子，NRF2 是抗氧化反应途径的关键激活剂。这些肿瘤是 组织学上类似于富马酸水合酶（FH）缺陷型肾细胞癌，后者是由生殖细胞中的种系突变引起的 FH基因。 FH 或 KEAP1 功能丧失可以激活 NRF2 通路。卡罗博士假设， 与 FH 类似，KEAP1 功能丧失种系变异会增加 RCC 风险，并且 KEAP1 突变 以 NRF2 依赖性方式促进 RCC 的发展。卡洛博士的目标是 (1) 描述 使用基因组、转录组和代谢技术分析 KEAP1 突变的 RCC，以及 (2) 描绘 KEAP1 和 FH 突变对 RCC 模型系统恶性转化的影响。首要的 目标是阐明肾细胞癌中种系和体细胞 KEAP1 突变对癌症的作用和影响 筛选并开发合理的靶向治疗。