The mechanisms driving brain oncogenesis by FGFR-TACC gene fusions

FGFR-TACC 基因融合驱动脑肿瘤发生的机制

基本信息

批准号：
8884561
负责人：
Antonio Iavarone
金额：
$ 37.28万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2014-07-02 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884561
关键词：
Adult Aftercare Aneuploidy Antineoplastic Agents Astrocytes Attention Automobile Driving Biochemical Biological Brain Brain Neoplasms Candidate Disease Gene Cell fusion Cells Childhood Chimeric Proteins Chromosomal Instability Chromosomal translocation Chromosome Segregation Chromosomes Clinical Clinical Trials Complement Data Defect Dependency Diagnostic Disease Outcome Dissection Dominant Genetic Conditions Engineering Epithelial Event FGFR3 gene Fibroblast Growth Factor Fibroblast Growth Factor Receptors Foundations Gene Fusion Gene Mutation Gene Silencing Generations Genes Genetic Genomics Glioblastoma Goals Growth Head and Neck Cancer Health Hematologic Neoplasms Human Human Characteristics Investigation Knock-in Mouse Knowledge Lesion Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of urinary bladder Mitosis Mitotic Mitotic spindle Modeling Molecular Mouse Strains Mutation Non-Small-Cell Lung Carcinoma Normal Cell Oncogenic Outcome Patients Phenotype Phosphorylation Phosphotransferases Protein Tyrosine Kinase Proteins Proteome Proteomics Recording of previous events Recurrence Reporting Signal Transduction Somatic Mutation Subgroup System TACC3 gene Testing Therapeutic Tissues Translating Tumor Subtype Tyrosine Tyrosine Phosphorylation Validation antitumor effect base biochemical tools cancer cell cancer genetics dynactin fitness gain of function gain of function mutation in vivo inhibitor/antagonist innovation man mouse model neoplastic cell novel novel therapeutics oncogene addiction personalized cancer therapy personalized medicine pre-clinical research study segregation targeted cancer therapy therapeutic target tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The history of successful targeted therapy of cancer largely coincides with the inactivation of recurrent and oncogenic gene fusions in hematological malignancies and recently in some types of epithelial cancer. Glioblastoma multiforme (GBM) is among the most lethal and incurable forms of human cancer and targeted therapies against common genetic alterations in GBM have not changed the dismal clinical outcome of the disease. We have recently identified FGFR-TACC gene fusions as the first example of highly oncogenic and recurrent gene fusions in GBM, targeted their dependency in a particular tumor subtype, and observed dramatic anti-tumor effects. This line of investigation has recently matured towards a clinical trial. The same gene fusions have recently been identified in several other tumor types, thus establishing FGFR-TACC fusions as one of the most frequent chromosomal translocations in human cancer. From a mechanistic standpoint, we have discovered the unexpected capacity of FGFR-TACC fusions to trigger aberrant segregation of chromosomes during mitosis, thus initiating chromosomal instability (CIN) and aneuploidy, two hallmarks of human cancer. However, we still have incomplete understanding of the full repertoire of the oncogenic activities of FGFR-TACC fusions and the extent to which FGFR-TACC fusions in human GBM trigger growth-promoting signals and aneuploidy. The central objective of this proposal is to decipher how mechanistically FGFR-TACC fusion proteins promote malignant transformation. Our central hypothesis is that the FGFR-TACC fusion protein, through an aberrant mislocalization of a constitutively active tyrosine kinase (FGFR) over the mitotic spindle pole, disrupts proper chromosome segregation in mitosis and that this novel function represents a critical event for brain tumor initiation. This primary activity of FGF-TACC fusions is likely to cooperate with other growth-promoting signaling functions that complement the reduced cellular fitness associated with loss of mitotic fidelity and aneuploidy, to induce full-blown-tumorigenesis. To identify the mechanistic determinants of brain tumor initiation and CIN instigated by FGFR-TACC fusions, this proposal will pursue three specific aims. In the first aim, we will identify the tyrosine phosphorylation landscape of substrates directly modified by the aberrant kinase activity of FGFR- TACC fusion proteins. In the second aim, we will determine the mechanism by which FGFR-TACC fusions disrupt proper chromosome segregation. In the third aim, we will model the CIN, growth promoting signaling functions and tumor initiating capacity of the FGFR3-TACC3 fusion in a conditional knock-in mouse strain that ex- presses the FGFR3-TACC3 protein in selected cells. The expected overall impact of this innovative proposal is that it will fundamentally advance our mechanistic understanding of FGFR-TACC fusions and lay the foundation for the optimization of the new therapeutic strategies that have been precipitated by the discovery of FGFR-TACC gene fusions in human cancer.

描述（由申请人提供）：癌症成功靶向治疗的历史在很大程度上与血液恶性肿瘤中复发性和致癌基因融合的失活以及最近在某些类型的上皮癌中相吻合。胶质母细胞瘤多形（GBM）是人类癌症的最致命和无法治愈的形式之一，针对GBM中常见遗传改变的靶向疗法并没有改变疾病的沮丧临床结果。我们最近将FGFR-TACC基因融合识别为GBM中高度致癌和复发基因融合的第一个例子，以它们在特定的肿瘤亚型中的依赖性，并观察到剧烈的抗肿瘤作用。这一调查方法最近已经成长为临床试验。最近在其他几种肿瘤类型中发现了相同的基因融合，因此将FGFR-TACC融合成为人类癌症中最常见的染色体易位之一。从机械的角度来看，我们发现了FGFR-TACC融合在有丝分裂过程中引发染色体异常隔离的意外能力，从而启动了染色体不稳定性（CIN）和非整倍性，这是人类癌症的两个特征。但是，我们仍然对FGFR-TACC融合的致癌活性以及人类GBM中FGFR-TACC融合的程度不完整，对人GBM触发生长促进信号和非整倍性的程度。该提案的核心目的是破译机械学上FGFR-TACC融合蛋白如何促进恶性转化。我们的中心假设是，FGFR-TACC融合蛋白通过在有丝分裂纺锤体上的组成型活性酪氨酸激酶（FGFR）的异常定位，破坏有丝分裂中的适当染色体分离，并且这种新颖的功能代表了脑瘤肿瘤起始启动的关键事件。 FGF-TACC融合的主要活性可能与其他促进生长的信号传导函数合作，这些信号传导功能补充了与有丝分裂保真度和非整倍性丧失相关的细胞适应性，以诱导全面的肿瘤发生。为了确定FGFR-TACC融合的脑肿瘤起始和CIN的机械决定因素，该提案将追求三个特定的目标。在第一个目的中，我们将确定通过FGFR-TACC融合蛋白的异常激酶活性直接修饰的底物的酪氨酸磷酸化景观。在第二个目标中，我们将确定FGFR-TACC融合破坏适当的染色体分离的机制。在第三个目标中，我们将在有条件的敲入小鼠菌株中对CIN进行建模，促进FGFR3-TACC3融合的肿瘤启动能力的增长能力，该型小鼠菌株在选定的细胞中按下FGFR3-TACC3蛋白。这项创新提案的预期总体影响是，它将从根本上提高我们对FGFR-TACC融合的机械理解，并为通过发现FGFR-TACC基因融合而在人类癌症中促进新的治疗策略的优化奠定了基础。。