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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.

项目总结