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

基本信息

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
项目类别：
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

项目摘要

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）：口腔癌口腔鳞状细胞癌（OSCC）的复发性FAT1突变和缺失是一种致命的疾病，尽管这些肿瘤中发生的遗传变化的目录不断扩大且越来越全面。在基因组后时代，OSCC的治疗进展需要系统的研究，通过将癌症基因与癌症过程以及癌症过程与获得的脆弱性联系起来来缩小差距。最近，在头和颈部鳞状细胞癌（HNSCC）中发现了影响基因FAT1的复发突变和缺失。在TP53之后，FAT1是HNSCC中的第二个流行基因突变。尚未探索FAT1功能丧失在OSCC，其细胞和临床后果以及它产生的任何潜在脆弱性的确切机制。我们的长期目标是将癌症基因组数据的股息转化为精确疗法的新途径，通过剖析口服和头颈癌的分子改变。候选人的长期目标是作为临床医生科学家发展研究职业，他能够独立地进行基因组发现，先进的生物信息学分析以及对驱动OSCC的遗传过程的功能分子研究。作为朝着这些长期目标的第一步，该提案的目的是详细介绍30％的口服癌症中丧失该基因的口服癌症的功能。 2013年，候选人首先报道了包括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，这是人类癌症4q35.2的广泛缺失的靶标。最近，PAN-CACTER分析已确定FAT1是21种癌症中最常见的基因最常见的基因。基于我们的初步数据，我们假设Fat1灭活的OSCC是一个独特的恶性亚型，由上调的Wnt信号传导和改变的鳞状谱系分化，并显示独特的临床行为。这项研究的理由是，了解FAT1灭活的OSCC将为精确的临床试验设计提供信息，并立即使用TARGEED剂直接进行临床研究。我们有以下3个具体目标。在AIM 1中，我们将剖析OSCC中FAT1失活的后果，重点是细胞行为，改变的癌症信号通路和治疗脆弱性。在AIM 2中，我们将研究灭活同时靶向FAT1和其他鳞状分化基因，对OSCC发育和侵略性的影响。在AIM 3中，我们将在其他临床协变量的背景下确定OSCC中FAT1失活的预后分析。这些研究将使用体外进行以及OSCC的体内模型和原发性患者样品。这项创新的工作将证明针对OSCC中迄今未经考虑的生物学过程的治疗潜力。在培训期间，候选人将通过实质性的实践经验和正式培训来熟练熟练精通生物信息学技术和鼠标建模。候选人将在主要导师蒂莫西·陈（Timothy Chan）博士的密切指导下完成研究和培训计划，这是一位出色的癌症基因组学研究员纪念斯隆 - 凯特林癌症中心（MSKCC）。此外，专家指导将由一个联席会员团队提供，他们包括MSKCC的James Fagin博士，MSKCC是癌症和信号转导网络的转基因小鼠模型专家；威尔·康奈尔医学院（Weill Cornell Medical College）的Andrew Dannenberg博士是致癌物诱导肿瘤动物模型的专家；以及纽约大学的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判以及对出版物，演示和赠款写作的战略意见来提供有关科学发展的意见。该候选人在世界领先的癌症研究中心拥有丰富的研究环境，并获得了临床主持人，研究部门领导力和机构的支持。总之，该提案的完成将使OSCC和HNSCC基因组学和癌症生物学独立职业的候选人定位。