Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland

唾液腺中 CRTC1-MAML2 融合癌蛋白的信号传导和靶向

• 批准号: 10439473
• 负责人: Lizi Wu
• 金额: $ 35.15万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439473
• 关键词: Antisense Oligonucleotides; Automobile Driving; Biology; CREB1 gene; Cell Survival; Cells; Chimeric Proteins; Cyclic AMP; Data; Development; Diagnostic; Disease; Dominant-Negative Mutation; Funding; Fusion Oncogene Proteins; Genes; Genetic Transcription; Genetically Engineered Mouse; Growth; Human; Impairment; In Vitro; Investigation; Lead; MLL/ELL; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of salivary gland; Metastatic/Recurrent; Modeling; Molecular; Mucoepidermoid Carcinoma; Oncogenes; Oncogenic; Outcome; Pathway interactions; Patients; Pattern; Permeability; Recurrence; Regulator Genes; Research; Role; Salivary Glands; Signal Transduction; Specificity; Testing; Therapeutic; Tissues; Transgenic Mice; Untranslated RNA; Xenograft procedure; activating transcription factor; cell growth; design; diagnostic biomarker; fusion gene; in vivo; in vivo evaluation; insight; mouse model; novel; novel diagnostics; novel strategies; novel therapeutic intervention; programs; protein protein interaction; prototype; small hairpin RNA; stapled peptide; targeted treatment; therapeutic target; transcription factor; tumor; tumorigenesis

Project Summary/Abstract This proposal focuses on the oncogenic CRTC1-MAML2 fusion that underlies the development of mucoepidermoid carcinomas (MEC), the most common type of salivary gland cancers. Patients with advanced, metastatic and recurrent MECs have poor outcomes and no targeted therapy is currently available. A comprehensive understanding of functions and mechanisms of this oncogenic fusion is essential for uncovering effective diagnostic and therapeutic approaches. We demonstrated that the CRTC1-MAML2 fusion is a major driver for MEC initiation and maintenance. Our investigations into the CRTC1-MAML2-induced oncogenic transcriptional program implicated long noncoding RNAs (lncRNAs) in MEC tumorigenesis and maintenance. LncRNAs belong to a novel class of gene regulators with emerging roles in human cancer and have the potential to serve as diagnostic markers due to their tissue and disease specificity. However, the involvement and mechanistic basis of lncRNAs remain poorly defined in MEC. Moreover, our data revealed the interaction of the CRTC1-MAML2 fusion with the transcription factor CREB is critical for inducing the major oncogenic transcriptional program; thus, targeting this interaction interface will have the advantage of blocking multiple critical fusion target genes/pathways. However, the significance of this fusion interaction as a therapeutic target remains to be tested in vivo. Therefore, the objectives of this proposal are to elucidate the lncRNA aspect of the oncogenic transcriptional program in CRTC1-MAML2- driven MEC and the significance of the critical fusion protein interaction governing the oncogenic transcriptional program in MEC. Two aims are proposed to test the overall hypothesis that the CRTC1-MAM2 fusion induces a unique lncRNA program in promoting MEC and that the CRTC1-MAML2/CREB interaction is critical for inducing the major oncogenic transcriptional program in MEC. Consequently, critical lncRNAs and fusion interaction can be targeted for MEC inhibition. Aim 1 will investigate the mechanisms and targeting of lncRNAs in CRTC1- MAML2 fusion-driven tumorigenesis. Aim 2 will Investigate the significance and targeting of the CRTC1-MAML2 fusion/CREB interaction in MEC. The completion of these proposed studies will uncover new mechanistic and functional insights into lncRNAs and the CRTC1-MAML2 oncogenic fusion and reveal new approaches for blocking MEC. We anticipate that these efforts will enhance our understanding of the CRTC1-MAML2 fusion oncogene and MEC biology and lead to the identification of novel diagnostic and therapeutic strategies.

项目摘要/摘要 该提案着重于致癌CRTC1-MAML2融合，该融合是基础的 粘膜表皮类癌（MEC），这是最常见的唾液腺癌类型。患者晚期 转移性MEC和复发性MEC的预后差，目前尚无靶向疗法。一个 对这种致癌融合的功能和机制的全面理解对于发现 有效的诊断和治疗方法。 我们证明了CRTC1-MAML2融合是MEC启动和维护的主要驱动力。 我们对CRTC1-MAML2诱导的致癌转录程序的调查涉及长期 MEC肿瘤发生和维持中的非编码RNA（LNCRNA）。 lncrnas属于一种新颖的基因 在人类癌症中具有新兴角色的调节剂，并且有可能作为诊断标记 它们的组织和疾病特异性。但是，LNCRNA的参与和机械基础仍然很差 在MEC中定义。此外，我们的数据揭示了CRTC1-MAML2融合与转录的相互作用 因子Creb对于诱导主要的致癌转录程序至关重要。因此，针对这种相互作用 界面将具有阻止多个关键融合靶基因/途径的优势。但是， 这种融合相互作用作为治疗靶标的意义仍有待在体内进行测试。因此，目标 该提议的旨在阐明CRTC1-MAML2-中致癌转录程序的LNCRNA方面 驱动的MEC及关键融合蛋白相互作用的重要性 MEC的程序。提出了两个目标来检验CRTC1-MAM2融合诱导A的总体假设 促进MEC的独特LNCRNA计划，CRTC1-MAML2/CREB相互作用对于诱导至关重要 MEC中主要的致癌转录程序。因此，关键的LNCRNA和融合相互作用可以 针对MEC抑制。 AIM 1将研究CRTC1-中lncRNA的机理和靶向 MAML2融合驱动的肿瘤发生。 AIM 2将研究CRTC1-MAML2的重要性和靶向 MEC中的融合/CREB相互作用。这些拟议的研究的完成将发现新的机理，并 对LNCRNA和CRTC1-MAML2致癌融合的功能见解，并揭示了新的方法 阻止MEC。我们预计这些努力将增强我们对CRTC1-MAML2融合的理解 癌基因和MEC生物学，并导致鉴定新的诊断和治疗策略。