Signaling and targeting of CRTC1-MAML2 fusion oncoprotein in salivary gland tumor

CRTC1-MAML2融合癌蛋白在唾液腺肿瘤中的信号传导和靶向

• 批准号: 8907995
• 负责人: Lizi Wu
• 金额: $ 37.65万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8907995
• 关键词: Accounting; Address; Aging; Angiogenic Factor; Animal Model; Arts; Biochemical; Biological Assay; Biology; CREB1 gene; Candidate Disease Gene; Data; Defect; Development; Educational workshop; Epithelial Cells; Event; Gene Targeting; Genetic Transcription; Goals; Growth; Health; Histologic; Human; In Vitro; MLL/ELL; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of salivary gland; Mediating; Mediator of activation protein; Metabolism; Microarray Analysis; Molecular; Monitor; Mucoepidermoid Carcinoma; Mus; Mutation; National Institute of Dental and Craniofacial Research; Nuclear Orphan Receptor; Oncogene Proteins; Oncogenes; Oncogenic; Organ; Pathogenesis; Pathway interactions; Patients; Pre-Clinical Model; Recurrence; Regulation; Role; Salivary Gland Neoplasms; Salivary Glands; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Transgenic Mice; Translations; Treatment outcome; Tumor Angiogenesis; Tumorigenicity; Unresectable; VEGFA gene; Work; activating transcription factor; angiogenesis; bioluminescence imaging; carcinogenesis; improved; in vitro Assay; in vivo; insight; malignant phenotype; mouse model; new therapeutic target; notch protein; novel; novel diagnostics; novel therapeutic intervention; protein complex; therapeutic target; tumor; tumor initiation; tumor progression; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and also arises in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. We were the first to clone a novel fusion oncogene, CRTC1-MAML2 from a recurrent t(11;19)(q14-21;p12-13) in malignant MEC cells. CRTC1 is a transcriptional co-activator for CREB-mediated transcription with newly discovered roles in metabolism, aging, and cancer, whereas MAML2 is a transcriptional co-activator for the Notch pathway with critical functions in development and cancer. The CRTC1-MAML2 fusion oncogene is associated with more than 50% of human MEC cases and represents a potential major etiologic molecular defect for MEC. Although NCI and NIDCR had identified the development of a mouse model to study CRTC1-MAML2 biology as a high-priority goal, there had been no progress since the First Salivary Gland Cancer Workshop in 2006. The goal of this project is to bridge this significant gap by characterizing the first animal model for CRTC1-MAML2 tumorigenicity. This exciting project will elucidate the role and mechanisms of CRTC1-MAML2 and explore approaches to block downstream oncogenic signals. We previously showed that the CRTC1-MAML2 has strong transcriptional co-activator activity and is capable of transforming epithelial cells in vitro, in art through co-activating the transcription factor CREB. Our recent preliminary studies indicate that depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and thus serves as a promising therapeutic target. A better understanding of the biology of this fusion oncogene will provide new targeting opportunities to block MEC. However, the critical mediators and the in vivo roles of this fusion oncogene in the development and progression of MEC remain poorly elucidated. We have generated exciting, significant preliminary data to support our central hypothesis of this proposal: the CRTC1-MAML2 fusion oncogene has critical roles in MEC pathogenesis through the aberrant activation of target genes and pathways; consequently, the targeting of fusion-induced abnormal signaling is effective in blocking fusion-positive MEC. This hypothesis will be addressed by three specific aims. Aim 1 will assess the in vivo roles of CRTC1-MAML2 fusion oncogene in MEC tumorigenesis using our newly developed conditional CRTC1-MAML2 mouse model. Aim 2 will validate the CRTC1-MAML2-regulated target genes and investigate the importance of aberrantly activated CRTC1-MAML2-dependent cell signaling in the maintenance of MEC. Aim 3 will functionally characterize the novel CRTC1-MAML2/ERR? interaction focusing on its role in regulating tumor angiogenesis. The successful completion of these aims will significantly increase our understanding of the biology of salivary gland tumors, and importantly, may identify novel CRTC1-MAML2-specific therapeutic targets.

描述（由申请人提供）：粘膜外皮类癌（MEC）是最常见的唾液腺恶性肿瘤，并且在其他多个器官部位也会出现。目前，患有晚期，无法切除的MEC的患者的治疗选择有限，治疗结果不佳。我们是第一个在恶性MEC细胞中重复t（11; 19）（Q14-21; p12-13）中克隆新型融合癌基因CRTC1-MAML2的人。 CRTC1是用于CREB介导的转录的转录共激活因子，在新陈代谢，衰老和癌症中具有新发现的作用，而MAML2是具有关键功能在发育和癌症中的关键功能的Notch途径的转录共激活因子。 CRTC1-MAML2融合癌基因与超过50％的人MEC病例有关，代表了MEC的潜在主要病因学分子缺损。尽管NCI和NIDCR已经确定了小鼠模型的发展来研究CRTC1-MAML2生物学是一个高优先级的目标，但自2006年第一个唾液腺癌症研讨会以来，这一目标是没有进步的。该项目的目的是通过表征CRTC1-MAML2碰撞的第一个动物模型来弥合这一重大差距。这个令人兴奋的项目将阐明CRTC1-MAML2的作用和机制，并探索阻断下游致癌信号的方法。我们先前表明，CRTC1-MAML2具有很强的转录共激活因子活性，并且能够通过共同激活转录因子CREB在ART中转化上皮细胞。我们最近的初步研究表明，当在体外测定或在体内传播为异种移植肿瘤时，CRTC1-MAML2融合表达的耗竭可降低人类恶性MEC细胞的生长和存活。这些发现表明，CRTC1-MAML2对于维持MEC恶性表型至关重要，因此是有前途的治疗靶标。更好地了解这种融合癌基因的生物学将为阻止MEC提供新的目标机会。但是，这种融合癌基因在MEC发展和进展中的关键介体和体内作用仍然很差。我们已经产生了令人兴奋的，重要的初步数据，以支持我们对该提案的中心假设：CRTC1-MAML2融合癌基因通过靶基因和途径的异常激活，在MEC发病机理中具有关键作用；因此，融合诱导的异常信号传导的靶向有效地阻断融合阳性MEC。该假设将由三个具体目标解决。 AIM 1将使用我们新开发的条件CRTC1-MAML2小鼠模型评估CRTC1-MAML2融合癌基因在MEC肿瘤发生中的体内作用。 AIM 2将验证CRTC1-MAML2调节的靶基因，并研究异常激活的CRTC1-MAML2依赖性细胞信号在MEC维持中的重要性。 AIM 3在功能上会表征新颖的CRTC1-MAML2/ERR？相互作用着重于其在调节肿瘤血管生成中的作用。这些目标的成功完成将显着提高我们对唾液腺肿瘤生物学的理解，并且重要的是，可以鉴定出新型的CRTC1-MAML2特异性治疗靶标。