Mechanisms of Adenoid Cystic Carcinoma Development and Tumor Maintenance

腺样囊性癌发生和肿瘤维持的机制

• 批准号: 9708228
• 负责人: CARLOS CAULIN
• 金额: $ 21.49万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9708228
• 关键词: 1p36; Address; Adenoid Cystic Carcinoma; Affect; Alleles; Biological; Biology; Cell Line; 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; Proteins; Protocols documentation; Recurrence; Reporting; Role; Salivary; Salivary Glands; Signal Transduction; Stem cells; System; Testing; Tetracyclines; Tissues; Transcription Repressor/Corepressor; 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; outcome forecast; overexpression; perineural; preclinical study; recombinase-mediated cassette exchange; salivary cell; targeted cancer therapy; therapy design; tool; transcriptome; tumor; tumor growth

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.

项目摘要 腺样性囊性癌（ACC）是唾液腺中第二常见的恶性肿瘤。超过60％ ACC患者在诊断后的15年内屈服于该疾病。缺乏可靠的实验模型 因为ACC限制了我们在理解疾病生物学和临床前的生物学方面的进展 测试新疗法的研究。在此提案中，我们通过提出产生来满足这一基本需求 基因工程的小鼠模型，它们会开发自动摄入ACC。这些老鼠将有助于确定角色 在人类ACC中经常发现的分子改变，并将产生一个分子的体内平台 和临床前研究，将有助于进步更有效地治疗ACC患者。 Myb在 在人类ACC中最常见的基因最常见，因为超过70％的肿瘤过表达MYB-NFIB融合 或全长myb。我们的初步研究表明，转基因小鼠的MYB过表达诱导ACC 长期延迟，表明MYB促进了ACC的开发，但也暗示了其他 ACC开发需要改变。发现影响MYB无关基因的遗传改变 人类ACC中的较低频率。值得注意的是，不同基因的突变预测会导致激活 在25％-35％的人类ACC中发现Notch信号传导，包括Notch1中的激活突变， 与预后不良有关。其中，在大约20％ ACC。 Spen是Notch信号传导的转录阻遏物，并通过 缺口依赖性和独立的机制。重要的是，这些突变与MYB共存 改变，但是它们对ACC开发的贡献目前尚不清楚。在此提案中，我们将分析 在ACC开发过程中，MYB与Notch激活或SPEN失活的合作，在鼠标模型中 这允许激活唾液腺中的突变。用于激活这些系统的系统的诱导性质 改变将使我们能够确定是否需要维持肿瘤生长并确定 肿瘤回归涉及的机制。分析在这些肿瘤中发展的转录组 小鼠将使我们能够识别有助于ACC开发的MYB调节的基因和途径 可能需要维持肿瘤生长，因此可能是探索新疗法的绝佳目标 对于ACC。