Functionalizing recurrent FAT1 mutations and deletions in oral cancer

口腔鳞状细胞癌（OSCC）是一种致死性疾病，尽管在这些肿瘤中发生的遗传改变的目录不断扩大和越来越全面，但存活率已经停滞。在后基因组时代，口腔鳞状细胞癌的治疗进展需要系统的研究，通过将癌症基因与癌症过程联系起来，以及将癌症过程与获得性脆弱性联系起来来弥补差距。最近，在头颈部鳞状细胞癌（HNSCC）中发现了影响FAT 1基因的复发性突变和缺失。在TP 53之后，FAT 1是HNSCC中第二常见的基因突变。FAT 1功能丧失在OSCC中发挥作用的确切机制、其细胞和临床后果以及其产生的任何潜在脆弱性尚未探索。我们的长期目标是将癌症基因组数据的红利转化为精确治疗的新途径，通过功能性解剖口腔和头颈癌的分子改变。候选人的长期目标是发展作为临床科学家的研究生涯，能够独立进行基因组发现，先进的生物信息学分析和驱动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30%的口腔癌中FAT 1基因失活的功能。2013年，该候选人首次报道了包括OSCC在内的多种癌症类型中存在复发性FAT 1突变，并表明FAT 1作为肿瘤抑制基因发挥作用，该基因是人类癌症中广泛缺失4q35.2的靶点。最近，泛癌症分析已经将FAT 1确定为21种癌症中第7大最常见的突变基因。基于我们的初步数据，我们假设FAT 1失活的口腔鳞癌是一种独特的恶性肿瘤亚型，由上调的Wnt信号和改变的鳞状细胞系分化驱动，并显示出独特的临床行为。这项研究的基本原理是，了解FAT 1失活的口腔鳞癌将告知精确的临床试验设计，并立即指导临床前研究与靶向药物。我们有以下三个具体目标。在目标1中，我们将剖析FAT 1失活在口腔鳞状细胞癌中的后果，重点关注细胞行为、改变的癌症信号通路和治疗弱点。在目标2中，我们将研究同时靶向FAT 1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，确定口腔鳞癌中FAT 1失活的预后后果。这些研究将使用体外 以及OSCC的体内模型和原始患者样品。这项创新性的工作将展示针对迄今为止未被考虑的口腔鳞癌生物过程的治疗潜力。在培训期间，候选人将通过大量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Memorial Sloan-Kettering癌症中心（MSKCC）的主要导师Timothy Chan博士的密切指导下完成，他是一位成功的癌症基因组学研究人员。此外，专家指导将由一组共同导师提供，他们包括MSKCC的James Fagin博士，癌症和信号转导网络转基因小鼠模型专家; Weill Cornell医学院的Andrew Dannenberg博士，致癌物诱导肿瘤动物模型专家;以及纽约大学的Brian施密特博士，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，演讲和赠款写作的战略投入，为科学发展提供投入。候选人在世界领先的癌症研究中心拥有丰富的研究环境，并得到临床主席，研究部门领导和机构的承诺支持。总之，完成本提案将定位候选人在OSCC和HNSCC基因组学和癌症生物学的独立职业生涯。

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.