权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目摘要融合基因是许多癌症中常见的染色体畸变，并且可以用作临床实践中的预后标志物和药物靶点。通过使用整个转录组通过测序，我们和其他人[1，2]已经在胶质母细胞瘤中发现了FGFR 3-TACC 3融合 (GBM)复发率高达8.3%融合，由一个串联重复事件引起的， 4p16.3在体外促进细胞增殖，在体内促进肿瘤进展。过表达星形胶质细胞的融合导致细胞非整倍性[1]，然而，促进细胞非整倍性的机制是不稳定的。染色体分离仍有待阐明。FGFR 3-TACC 3融合阳性细胞对MEK抑制剂U 0126或泛FGFR抑制剂PD 173074表现出更高的敏感性，对一线GBM化疗药物替莫唑胺（TMZ）更耐药。所以我们研究已经确定了GBM中的一种新的遗传改变，其对于至少两种主要的这种致命疾病的特征：基因组不稳定性和对化疗的抵抗力。最近的一报道显示FGFR 3-TACC 3融合也发生在膀胱癌中[3]。因此这一新发现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的FGFR 3-TACC 3癌基因。我们假设FGFR 3-TACC 3 融合蛋白是一种关键的遗传畸变，它显著地改变了信号通路在神经胶质瘤的发展和进展过程中促进GBM的标志。我们计划通过进行实验来测试我们的假设，这些实验将确定关键的磷酸化，融合物中促进肿瘤发展的位点和结构域，以确定肿瘤的发生发展。融合体对替莫唑胺治疗耐药的分子机制，以确定融合促进异常染色体分离的机制，以及为了确定目前的药理学抑制剂在治疗融合中的功效，肿瘤的我们将使用体外和体内方法来回答这些问题。