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

描述（由申请人提供）：粘液表皮样癌（MEC）是最常见的唾液腺恶性肿瘤，也发生在多个其他器官部位。目前，晚期、不可切除的MEC患者的治疗选择有限，治疗效果较差。我们是第一个从恶性MEC细胞中复发的t（11;19）（q14-21;p12-13）中克隆一种新的融合癌基因CRTC 1-MAML 2。CRTC 1是CREB介导的转录的转录共激活因子，在代谢、衰老和癌症中具有新发现的作用，而MAML 2是Notch途径的转录共激活因子，在发育和癌症中具有关键功能。CRTC 1-MAML 2融合癌基因与超过50%的人类MEC病例相关，并且代表MEC的潜在主要病因学分子缺陷。虽然NCI和NIDCR已经确定了研究CRTC 1-MAML 2生物学的小鼠模型的开发作为一个高度优先的目标，但自2006年第一次唾液腺癌研讨会以来没有取得任何进展。该项目的目标是通过表征CRTC 1-MAML 2致瘤性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CRTC 1-MAML 2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，CRTC 1-MAML 2具有强的转录共激活因子活性，并且能够在体外转化上皮细胞，在本领域中通过共激活转录因子CREB。我们最近的初步研究表明，CRTC 1-MAML 2融合表达的耗竭降低了人恶性MEC细胞的生长和存活，当在体外测定时或当作为异种移植肿瘤在体内繁殖时。这些发现表明CRTC 1-MAML 2在维持MEC恶性表型中是必不可少的，因此作为有希望的治疗靶点。更好地了解这种融合癌基因的生物学特性将为阻断MEC提供新的靶向机会。然而，该融合癌基因在MEC的发展和进展中的关键介质和体内作用仍不清楚。我们已经产生了令人兴奋的，重要的初步数据，以支持我们的中心假设的这一建议：CRTC 1-MAML 2融合癌基因具有关键作用，MEC的发病机制，通过异常激活的靶基因和途径，因此，融合诱导的异常信号的靶向是有效的，在阻断融合阳性MEC。这一假设将通过三个具体目标来解决。目的1利用我们新开发的条件性CRTC 1-MAML 2小鼠模型，研究CRTC 1-MAML 2融合癌基因在MEC肿瘤发生中的作用。目的2验证CRTC 1-MAML 2调控的靶基因，并研究异常激活的CRTC 1-MAML 2依赖的细胞信号传导在MEC维持中的重要性。目的3将功能性表征新的CRTC 1-MAML 2/ERR？相互作用，重点是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著增加我们对唾液腺肿瘤生物学的理解，重要的是，可以确定新的CRTC 1-MAML 2特异性治疗靶点。

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.