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

• 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
• 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

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（申请人提供）：融合基因是许多癌症中常见的染色体畸变，在临床实践中可作为预后标志物和药物靶点。通过使用全转录组测序，我们和其他人[1，2]已经发现胶质母细胞瘤（GBM）中的FGFR 3-TACC 3融合体的复发率高达8.3%。由4p16.3上的串联重复事件引起的融合促进了体外细胞增殖和体内肿瘤进展。融合蛋白在星形胶质细胞中的过表达导致细胞非整倍性[1]，然而促进异常染色体分离的机制仍有待阐明。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，但对一线GBM化疗药物替莫唑胺（TMZ）更具抗性。因此，我们的研究已经确定了GBM中的一种新的遗传改变，该改变对这种致命疾病的至少两个主要标志至关重要：基因组不稳定性和对化疗的抗性。最近的报告显示，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，它显著改变了胶质瘤发展和进展过程中的信号通路，从而导致GBM的特征。我们计划通过实验来验证我们的假设，这些实验将确定融合中促进肿瘤发展的关键磷酸化位点和结构域，以确定融合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，并最终确定当前药理学抑制剂在治疗含有融合的肿瘤中的功效。我们将使用体外和体内方法来回答这些问题。