Characterization of oncogenic FGFR3-TACC3 fusion gene in glioblastoma

胶质母细胞瘤中致癌 FGFR3-TACC3 融合基因的特征

基本信息

批准号：
8647779
负责人：
Wei Zhang
金额：
$ 39.84万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-09 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647779
关键词：
4p16.3 Aneuploidy Antibodies Astrocytes BCL1 Oncogene Biological Models C-terminal Cell Proliferation Cells Centrosome Chimeric Proteins Chromosome abnormality Development Disease Drug Targeting Event Exhibits FGFR3 gene Family member Fibroblast Growth Factor Receptors Genetic Genome Genomic Instability Glioblastoma Glioma In Vitro Investigation Lead MEKs Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Mitosis Mitotic Molecular Mus Mutation Oncogenes Oncogenic Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Site Pre-Clinical Model Prognostic Marker Recurrence Reporting Resistance STAT3 gene Signal Pathway TACC3 gene Testing Therapeutic Therapeutic Agents Therapeutic Intervention U-0126 Xenograft procedure base chemotherapy clinical practice combat cyclin B1 fusion gene human STK6 protein in vivo inhibitor/antagonist mouse model novel overexpression public health relevance research study segregation temozolomide therapeutic target transcriptome sequencing tumor tumor progression tumorigenesis

项目摘要

Project Summary Fusion genes are common chromosomal aberrations in many cancers, and can be used as prognostic markers and drug targets in clinical practice. By using whole transcriptome sequencing, we and others [1, 2] have discovered FGFR3-TACC3 fusions in glioblastoma (GBM) at a recurrence rate of up to 8.3%. The fusion, caused by a tandem duplication event on 4p16.3, promoted cell proliferation in vitro and tumor progression in vivo. Overexpression of the fusion in astrocytes lead to cellular aneuploidy [1], however the mechanisms facilitating aberrant chromosomal segregation remain to be elucidated. FGFR3-TACC3 fusion positive cells exhibited higher sensitivity to the MEK inhibitor U0126 or pan FGFR inhibitor PD173074 but were more resistant to the frontline GBM chemotherapy drug, Temozolomide (TMZ). Thus, our studies have identified a novel genetic alteration in GBM that is critical for at least two major hallmarks of this deadly disease: genomic instability and resistance to chemotherapy. A recent report showed that the FGFR3-TACC3 fusion also occurs in bladder cancer [3]. Thus, the significance of this newly recognized genetic event is likely broad. We seek to further characterize this novel FGFR3-TACC3 oncogene. We hypothesize that the FGFR3-TACC3 fusion protein is a key genetic aberration that significantly modifies the signaling pathways during glioma development and progression contributing to the hallmarks of GBM. We plan to test our hypothesis by performing experiments that will determine the critical phosphorylation sites and domains within the fusion that promote tumor development, to determine the molecular mechanisms by which the fusion is resistant to temozolomide treatment, to determine the mechanisms by which the fusion promotes abnormal chromosomal segregation, and finally to determine the efficacy of current pharmacological inhibitors in treating fusion containing tumors. We will use both in vitro and in vivo approaches to answer these questions.

项目概要融合基因是许多癌症中常见的染色体畸变，可用作临床实践中的预后标志物和药物靶点。通过使用全转录组通过测序，我们和其他人 [1, 2] 在胶质母细胞瘤中发现了 FGFR3-TACC3 融合 (GBM) 的复发率高达 8.3%。融合是由串联重复事件引起的 4p16.3，促进体外细胞增殖和体内肿瘤进展。过度表达星形胶质细胞中的融合导致细胞非整倍性[1]，然而促进异常的机制染色体分离仍有待阐明。 FGFR3-TACC3融合阳性细胞对 MEK 抑制剂 U0126 或泛 FGFR 抑制剂 PD173074 表现出更高的敏感性，但对一线 GBM 化疗药物替莫唑胺 (TMZ) 的耐药性更强。因此，我们的研究发现 GBM 中存在一种新的基因改变，该改变对于至少两个主要疾病至关重要这种致命疾病的特点是：基因组不稳定和对化疗的耐药性。最近的一个报告显示FGFR3-TACC3融合也发生在膀胱癌中[3]。因此，这一新认识的遗传事件的意义可能是广泛的。我们寻求进一步表征这种新型 FGFR3-TACC3 癌基因。我们假设 FGFR3-TACC3 融合蛋白是一种关键的遗传畸变，可显着改变信号通路在神经胶质瘤的发展和进展过程中，形成了 GBM 的特征。我们计划通过进行确定关键磷酸化的实验来检验我们的假设融合中促进肿瘤发展的位点和结构域，以确定融合对替莫唑胺治疗产生耐药性的分子机制，以确定融合促进异常染色体分离的机制，最后确定当前药物抑制剂治疗融合的功效肿瘤。我们将使用体外和体内方法来回答这些问题。