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：
8967572
负责人：
Wei Zhang
金额：
$ 1.25万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8967572
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 Health 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 Xenograft procedure base chemotherapy clinical practice combat cyclin B1 fusion gene in vivo inhibitor/antagonist mouse model novel overexpression research study segregation targeted treatment temozolomide transcriptome sequencing tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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 resistanc 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 treatin fusion containing tumors. We will use both in vitro and in vivo approaches to answer these questions.

描述（由申请人提供）：融合基因是许多癌症中常见的染色体畸变，可以用作临床实践中的预后标记和药物靶标。通过使用整个转录组测序，我们和其他[1，2]在胶质母细胞瘤（GBM）中发现了FGFR3-TACC3融合，复发率高达8.3％。融合是由4p16.3上的串联重复事件引起的，在体内促进了细胞增殖和肿瘤进展。星形胶质细胞中融合的过表达导致细胞非整倍性[1]，但是促进异常染色体隔离的机制仍有尚待阐明。 FGFR3-TACC3融合阳性细胞对MEK抑制剂U0126或PAN FGFR抑制剂PD173074表现出更高的敏感性，但对前线GBM化学疗法药物Temozolomide（TMZ）的耐药性更大。因此，我们的研究已经确定了GBM中新型的遗传改变，这对于这种致命疾病的至少两个主要标志至关重要：基因组不稳定性和抗化疗。最近的一份报告显示，FGFR3-TACC3融合也发生在膀胱癌中[3]。因此，这种新认识的遗传事件的意义可能很广。我们试图进一步描述这种新颖的FGFR3-TACC3癌基因。我们假设FGFR3-TACC3融合蛋白是一个关键的遗传畸变，它可以显着修改神经胶质瘤发育和进展过程中有助于GBM标志的信号通路。我们计划通过执行将确定促进肿瘤发展的融合中的关键磷酸化位点和结构域来测试假说，以确定融合对链酚剂治疗的抗性分子机制，从而确定融合促进异常色粒染色体的治疗效果的机制，以确定融合促进异常融合的效果，并促进了当前的效果。我们将使用体外和体内方法来回答这些问题。