Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance

腺样囊性癌发生和肿瘤维持的机制

基本信息

批准号：
10307053
负责人：
CARLOS CAULIN
金额：
$ 36.09万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307053
关键词：
1p36 Address Adenoid Cystic Carcinoma Affect Alleles Biological Biology Cell Line Cre lox recombination system Development Diagnosis Disease Distant Metastasis Epigenetic Process Experimental Models Frameshift Mutation Frequencies Gene Fusion Generations Genes Genetic Genetically Engineered Mouse Goals Growth Histologic Human Human Biology Immunotherapy Length Maintenance Malignant - descriptor Malignant Neoplasms Mammary gland Modeling Molecular Mus Mutate Mutation NFIB gene NOTCH1 gene Nature Neoplasm Metastasis Oncogenes Oncogenic Pathway interactions Patients Prognosis Proteins Protocols documentation Recurrence Reporting Role Salivary Salivary Glands Signal Transduction System Testing Tetracyclines Tissues Transcription Repressor Transgenes Transgenic Mice Treatment Efficacy Tumor Suppressor Proteins Variant cell stroma chromosome loss design effective therapy human disease in vivo loss of function mouse model neoplastic cell new therapeutic target notch protein novel therapeutics overexpression perineural preclinical study salivary cell stem cells targeted cancer therapy therapy design tool transcriptome tumor tumor growth

项目摘要

PROJECT SUMMARY Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the ACC patients succumb to the disease within 15 years from diagnosis. The lack of reliable experimental models for ACC has limited our progress in understanding the biology of the disease and the proliferation of preclinical studies to test new therapies. In this proposal we address this fundamental need by proposing the generation of genetically engineered mouse models that develop autochthonous ACCs. These mice will help determine the role of molecular alterations frequently found in human ACCs and will generate an in vivo platform for molecular and preclinical studies that will help advance towards more effective therapies to treat ACC patients. MYB is by far the most commonly altered gene in human ACCs, as over 70% of the tumors overexpress MYB-NFIB fusions or the full-length MYB. Our preliminary studies show that MYB overexpression in transgenic mice induces ACCs with long latency, indicating that MYB promotes ACC development, but also suggesting that additional alterations are required for ACC development. Genetic alterations affecting MYB-unrelated genes are found at lower frequencies in human ACCs. Notably, mutations in different genes that are predicted to result in activation of NOTCH signaling, including activating mutations in NOTCH1, were found in 25%-35% of the human ACCs, associated with poor prognosis. Of those, inactivating mutations in the SPEN gene were found in ~20% of the ACCs. SPEN is a transcriptional repressor of NOTCH signaling and functions as a tumor suppressor through NOTCH-dependent and NOTCH-independent mechanisms. Importantly, these mutations co-exist with MYB alterations, but their contribution to ACC development is presently unknown. In this proposal we will analyze the cooperation of MYB with NOTCH activation or SPEN inactivation during ACC development, in mouse models that allow the activation of mutations in salivary glands. The inducible nature of the system used to activate these alterations will allow us to determine whether they are required to maintain tumor growth and to identify mechanisms involved in tumor regression. Analysis of the transcriptomes of the tumors that develop in these mice will allow us to identify MYB-regulated genes and pathways that contribute to ACC development, some of which may be required to maintain tumor growth, and thus could be excellent targets to explore new therapies for ACC.

项目概要腺样囊性癌（ACC）是唾液腺第二常见的恶性肿瘤。超过60%的 ACC 患者在诊断后 15 年内死于该病。缺乏可靠的实验模型因为 ACC 限制了我们在了解该疾病的生物学和临床前病毒扩散方面的进展研究测试新疗法。在本提案中，我们通过提议生成来解决这一基本需求开发本地 ACC 的基因工程小鼠模型。这些小鼠将有助于确定角色人类 ACC 中常见的分子改变，并将产生一个分子改变的体内平台临床前研究将有助于开发更有效的疗法来治疗 ACC 患者。 MYB 是由到目前为止，人类 ACC 中最常改变的基因，因为超过 70% 的肿瘤过度表达 MYB-NFIB 融合或全长 MYB。我们的初步研究表明，转基因小鼠中 MYB 过度表达可诱导 ACC 潜伏期长，表明 MYB 促进 ACC 发育，但也表明额外的 ACC 开发需要进行更改。影响 MYB 无关基因的遗传改变被发现于人类 ACC 中的频率较低。值得注意的是，不同基因的突变预计会导致激活在 25%-35% 的人类 ACC 中发现了 NOTCH 信号传导，包括激活 NOTCH1 突变，与预后不良有关。其中，约 20% 的人发现了 SPEN 基因的失活突变。 ACC。 SPEN 是 NOTCH 信号传导的转录抑制因子，并通过以下方式发挥肿瘤抑制因子的作用： NOTCH 依赖和 NOTCH 独立机制。重要的是，这些突变与 MYB 共存改变，但它们对 ACC 发展的贡献目前尚不清楚。在这个提案中我们将分析在小鼠模型中，ACC 发育过程中 MYB 与 NOTCH 激活或 SPEN 失活的配合允许激活唾液腺突变。用于激活这些系统的诱导性质改变将使我们能够确定它们是否需要维持肿瘤生长并确定参与肿瘤消退的机制。对这些细胞中发生的肿瘤的转录组进行分析小鼠将使我们能够识别有助于 ACC 发育的 MYB 调节基因和途径，其中一些这可能是维持肿瘤生长所必需的，因此可能是探索新疗法的绝佳靶点对于ACC。