Role of MYB and MYB-NFIB fusions in Salivary Adenoid Cystic Carcinoma

MYB 和 MYB-NFIB 融合在唾液腺腺样囊性癌中的作用

• 批准号: 8701485
• 负责人: CARLOS CAULIN
• 金额: $ 24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701485
• 关键词: Adenoid Cystic Carcinoma; Adjuvant; Adult; Animal Model; Bioinformatics; Biology; Candidate Disease Gene; Cell Line; Clinical; Code; Collaborations; Communities; Cre-LoxP; Development; Disease; Disease Progression; Distant Metastasis; Event; Exons; Experimental Models; Future; Gene Expression; Gene Fusion; Gene Targeting; Generations; Genes; Growth; High Prevalence; Human; Human Biology; Human Cell Line; Knowledge; Laboratories; Lead; Length; Low Prevalence; MYB gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Molecular; Molecular Profiling; Mus; Mutation; NFIB gene; Nature; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome Study; Pathway interactions; Patients; Pre-Clinical Model; Protocols documentation; Radiation; Recurrence; Research; Resources; Role; Salivary; Salivary Glands; Survival Rate; System; Technology; Testing; Tetracyclines; Therapeutic; Transcript; Transgenic Mice; Tumor Suppressor Genes; Variant; base; cohort; design; exome sequencing; human NFIB protein; improved; in vivo; mouse model; new therapeutic target; novel; overexpression; prevent; public health relevance; response; therapy design; transgene expression; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the ACC patients succumb to the disease as a result of the persistent slow growth, high recurrence rates and propensity to distant metastasis. During the past decades little progress has been made in improving therapies to treat ACC patients, primarily due to the limited knowledge of the genetic alterations involved in ACC development and the lack of relevant experimental models for the disease. The recent discovery of the MYB- NFIB gene fusion in human ACCs has changed this outlook and stimulated new avenues of research that are expected to lead to novel and more effective therapeutic options for ACC patients. Our collaborative studies with Dr. Adel El-Naggar in MD Anderson, identified MYB-NFIB fusions in approximately 40% of the human salivary ACCs. In addition, we observed MYB overexpression in most of the fusion-positive tumors and over half of the ACCs in which the MYB gene was intact. Notably, recent exome sequencing of salivary ACCs confirmed the high rates of MYB alterations and the low prevalence of mutations in other oncogenes or tumor suppressor genes, further reinforcing the notion that salivary ACC is a malignancy driven by alterations in the MYB gene. Based on these clinical observations, in this proposal we will test the hypothesis that MYB overexpression, as part of the MYB-NFIB fusion or in the full-length form, is a primary oncogenic event in ACC development. To test this hypothesis, in Specific Aim 1 we will determine the oncogenic potential of MYB and MYB-NFIB in transgenic mice in which the MYB variants will be overexpressed exclusively in the salivary glands, using an inducible system optimized in our laboratory. To maximize the potential of these mouse models, a reversible inducible system will be generated to induce MYB and MYB-NFIB in salivary glands. Thus, these mice will allow us to determine whether suppression of the MYB or MYB-NFIB functions can promote regression of established tumors. These studies will provide the experimental support for the generation of new therapies designed to inactivate the oncogenic function of MYB or MYB-NFIB fusions to treat patients with ACC. In Specific Aim 2 we will identify MYB and MYB-NFIB target genes that contribute to their oncogenic potential and will determine whether MYB and MYB-NFIB regulate the expression of common and/or distinct targets genes in salivary glands. This analysis will uncover MYB-regulated genes with potential applications to targeted therapy for salivary ACC and will determine the potential of MYB profiling to personalize ACC treatment.

描述（由申请人提供）：腺样囊性癌（ACC）是唾液腺第二常见的恶性肿瘤。由于持续缓慢的生长、高复发率和远处转移倾向，超过60%的ACC患者死于该病。在过去的几十年里，在改善 ACC 患者的治疗方法方面几乎没有取得任何进展，这主要是由于对 ACC 发展所涉及的基因改变的了解有限，并且缺乏该疾病的相关实验模型。最近在人类 ACC 中发现的 MYB-NFIB 基因融合改变了这一前景，并激发了新的研究途径，有望为 ACC 患者带来新的、更有效的治疗选择。我们与 MD 安德森的 Adel El-Naggar 博士合作研究，在大约 40% 的人类唾液 ACC 中发现了 MYB-NFIB 融合。此外，我们在大多数融合阳性肿瘤和超过一半的 MYB 基因完整的 ACC 中观察到 MYB 过度表达。值得注意的是，最近唾液 ACC 的外显子组测序证实了 MYB 改变的高发生率以及其他癌基因或抑癌基因突变的低发生率，进一步强化了唾液 ACC 是由 MYB 基因改变驱动的恶性肿瘤的观点。基于这些临床观察，在本提案中，我们将检验以下假设：MYB 过度表达作为 MYB-NFIB 融合的一部分或全长形式，是 ACC 发育中的主要致癌事件。为了检验这一假设，在具体目标 1 中，我们将使用我们实验室优化的诱导系统，确定 MYB 和 MYB-NFIB 在转基因小鼠中的致癌潜力，其中 MYB 变体将仅在唾液腺中过度表达。为了最大限度地发挥这些小鼠模型的潜力，将产生一个可逆诱导系统来诱导唾液腺中的 MYB 和 MYB-NFIB。因此，这些小鼠将使我们能够确定 MYB 或 MYB-NFIB 功能的抑制是否可以促进已形成肿瘤的消退。这些研究将为开发旨在灭活 MYB 或 MYB-NFIB 融合的致癌功能以治疗 ACC 患者的新疗法提供实验支持。在具体目标 2 中，我们将鉴定有助于其致癌潜力的 MYB 和 MYB-NFIB 靶基因，并将确定 MYB 和 MYB-NFIB 是否调节唾液腺中常见和/或不同靶基因的表达。该分析将揭示 MYB 调节基因，这些基因可能应用于唾液 ACC 靶向治疗，并将确定 MYB 分析在个性化 ACC 治疗中的潜力。