Functionalizing recurrent FAT1 mutations and deletions in oral cancer

口腔癌中复发性 FAT1 突变和缺失的功能化

• 批准号: 9333111
• 负责人: Luc Gordon Trang Morris
• 金额: $ 13.64万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333111
• 关键词: 4q35; Affect; Animal Model; Automobile Driving; Award; Behavior; Bioinformatics; Biological Markers; Cancer Biology; Cancer Model; Carcinogens; Catalogs; Chromosome Deletion; Clinical; Clinical Trials Design; Critiques; Data; Data Analyses; Dependency; Development; Differentiated Gene; Disease; Environment; Experimental Designs; FAT gene; Gene Expression; Gene Mutation; Gene Silencing; Genes; Genetic; Genetic Processes; Genomics; Goals; Grant; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Human Papillomavirus; In Vitro; Institution; Investigation; Investigational Therapies; Knowledge; Leadership; Link; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Memorial Sloan-Kettering Cancer Center; Mentors; Molecular; Mutate; Mutation; NCI Center for Cancer Research; NOTCH1 gene; New York; Oncogenes; Oral; Pathway interactions; Patients; Portraits; Positioning Attribute; Precision therapeutics; Prevalence; Process; Program Development; Publications; Publishing; Recurrence; Reporting; Repression; Research; Research Personnel; Research Training; Sampling; Scientist; Seasons; Signal Pathway; Signal Transduction; Smoking Status; Squamous Cell; Squamous Differentiation; Squamous cell carcinoma; Stem cells; Survival Rate; TP53 gene; Techniques; Therapeutic; Time; Training; Transgenic Mice; Translating; Tumor Suppressor Genes; Universities; WNT Signaling Pathway; Work; Writing; anticancer research; base; cancer biomarkers; cancer genome; cancer genomics; cancer therapy; cancer type; career; career development; effective therapy; experience; gene function; in vivo Model; innovation; loss of function; malignant mouth neoplasm; medical schools; mouse model; mouth squamous cell carcinoma; notch protein; novel marker; novel therapeutics; outcome forecast; pre-clinical research; prognostic; programs; public health relevance; research and development; small molecule; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Functionalizing recurrent FAT1 mutations and deletions in oral cancer Oral squamous cell carcinoma (OSCC) is a lethal disease with survival rates that have stalled, despite an expanding and increasingly comprehensive catalog of the genetic alterations occurring in these tumors. In the post-genomic era, treatment advances in OSCC require systematic research that closes a gap by linking cancer genes to cancer processes, and cancer processes to acquired vulnerabilities. Recently, recurrent mutations and deletions affecting the gene FAT1 have been identified in head and neck squamous cell carcinoma (HNSCC). After TP53, FAT1 is the second-most prevalent gene mutation in HNSCC. The precise mechanism by which FAT1 loss-of-function operates in OSCC, its cellular and clinical consequences, and any potential vulnerabilities it engenders, have not been explored. Our long-term goal is to translate the dividend of cancer genome data into new avenues of precision therapy, by functionally dissecting molecular alterations in oral and head and neck cancer. The candidate's long term goal is to develop a research career as a clinician-scientist who is able to independently perform genomic discovery, advanced bioinformatic analyses, and functional molecular investigation of genetic processes that drive OSCC. As a first step toward these long-term goals, the objective of this proposal is to characterize, in detail, the function o FAT1 in the 30% of oral cancers harboring inactivation of this gene. In 2013, the candidate first reported the presence of recurrent FAT1 mutations in multiple cancer types, including OSCC, and showed that FAT1 functions as a tumor suppressor gene that is the target of widespread deletion of 4q35.2 in human cancer. More recently, pan-cancer analyses have identified FAT1 as the 7th most frequently mutated gene across 21 types of cancer. Based upon our preliminary data, we hypothesize that FAT1-inactivated OSCC is a distinct subtype of malignancy, driven by upregulated Wnt signaling and altered squamous lineage differentiation, and displaying unique clinical behavior. The rationale for this research is that understanding FAT1-inactivated OSCC will inform precise clinical trial design, and immediately direct pre- clinical research with targeed agents. We have the following 3 specific aims. In Aim 1, we will dissect the consequences of FAT1 inactivation in OSCC, focusing on cellular behavior, altered cancer signaling pathways, and therapeutic vulnerabilities. In Aim 2, we will examine the impact of inactivation concurrently targeting FAT1 and other squamous differentiation genes, on OSCC development and aggressiveness. In Aim 3, we will determine the prognostic ramifications of FAT1 inactivation in OSCC, in the context of other clinical covariates. These studies will be carried out using in vitro and in vivo models of OSCC, and primary patient samples. This innovative work will demonstrate the therapeutic potential of targeting heretofore unconsidered biologic processes in OSCC. During the training period, the candidate will gain proficiency in advanced bioinformatics techniques and mouse modeling through substantive hands-on experience and formal training. The research and training plan will be completed by the candidate under the close guidance of primary mentor Dr. Timothy Chan at Memorial Sloan-Kettering Cancer Center (MSKCC), who is an accomplished cancer genomics researcher. In addition, expert guidance will be provided by a team of co-mentors, who include Dr. James Fagin at MSKCC, an expert on transgenic mouse models of cancer and signal transduction networks; Dr. Andrew Dannenberg at Weill Cornell Medical College, an expert on animal models of carcinogen-induced tumors; and Dr. Brian Schmidt at New York University, an expert on oral cancer biomarkers. Together, the seasoned mentoring team also provides input on scientific development through critique of experimental design and data analysis, and strategic input on publications, presentations, and grant writing. The candidate has the benefit of a rich research environment at a world-leading cancer research center and the committed support of clinical chairs, research department leadership, and the institution. Altogether, completion of this proposal will position the candidate for an independent career in OSCC and HNSCC genomics and cancer biology.

描述（由申请人提供）：功能化口腔癌中复发性 FAT1 突变和缺失口腔鳞状细胞癌 (OSCC) 是一种致命疾病，尽管这些肿瘤中发生的基因改变目录不断扩大且日益全面，但其存活率已陷入停滞。在后基因组时代，口腔鳞癌的治疗进展需要系统研究，通过将癌症基因与癌症过程以及癌症过程与后天脆弱性联系起来来缩小差距。最近，在头颈鳞状细胞癌 (HNSCC) 中发现了影响 FAT1 基因的反复突变和缺失。 FAT1 是继 TP53 之后，HNSCC 中第二常见的基因突变。 FAT1 功能丧失在 OSCC 中的精确机制、其细胞和临床后果以及它产生的任何潜在漏洞尚未得到探索。我们的长期目标是通过功能性剖析口腔癌和头颈癌的分子变化，将癌症基因组数据的红利转化为精准治疗的新途径。候选人的长期目标是发展成为一名临床医生科学家的研究职业，能够独立进行基因组发现、先进的生物信息学分析以及驱动 OSCC 的遗传过程的功能分子研究。作为实现这些长期目标的第一步，本提案的目的是详细描述 FAT1 在 30% 的口腔癌中的功能，该基因失活。 2013年，该候选者首次报告了包括OSCC在内的多种癌症类型中存在复发性FAT1突变，并表明FAT1作为肿瘤抑制基因发挥作用，该基因是人类癌症中4q35.2广泛缺失的目标。最近，泛癌症分析已确定 FAT1 是 21 种癌症中第七大最常见突变基因。根据我们的初步数据，我们假设 FAT1 失活的 OSCC 是一种独特的恶性肿瘤亚型，由 Wnt 信号传导上调和鳞状谱系分化改变驱动，并表现出独特的临床行为。这项研究的基本原理是，了解 FAT1 失活的 OSCC 将为精确的临床试验设计提供信息，并立即指导靶向药物的临床前研究。我们有以下 3 个具体目标。在目标 1 中，我们将剖析 FAT1 失活对 OSCC 的影响，重点关注细胞行为、癌症信号传导途径的改变和治疗脆弱性。在目标 2 中，我们将研究同时针对 FAT1 和其他鳞状分化基因的失活对 OSCC 发展和侵袭性的影响。在目标 3 中，我们将在其他临床协变量的背景下确定 OSCC 中 FAT1 失活的预后影响。这些研究将在体外进行 以及 OSCC 的体内模型和主要患者样本。这项创新工作将展示针对 OSCC 中迄今为止未被考虑的生物过程的治疗潜力。在培训期间，候选人将通过实质性的实践经验和正式培训，熟练掌握先进的生物信息学技术和小鼠建模。研究和培训计划将由候选人在纪念斯隆-凯特琳癌症中心 (MSKCC) 的主要导师 Timothy Chan 博士的密切指导下完成，Timothy Chan 博士是一位出色的癌症基因组学研究员。此外，联合导师团队将提供专家指导，其中包括 MSKCC 的 James Fagin 博士，他是癌症转基因小鼠模型和信号转导网络方面的专家；威尔康奈尔医学院的Andrew Dannenberg博士，致癌物诱发肿瘤动物模型专家；纽约大学的 Brian Schmidt 博士是口腔癌生物标志物专家。经验丰富的指导团队还通过对实验设计和数据分析的批评，以及对出版物、演示和资助写作的战略投入，为科学发展提供投入。候选人受益于世界领先的癌症研究中心丰富的研究环境以及临床主席、研究部门领导和机构的坚定支持。总而言之，完成该提案将使候选人能够在 OSCC 和 HNSCC 基因组学和癌症生物学领域从事独立职业。