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Role of the Sterile20 (Ste20)-like kinase MST4 in Pituitary Tumorigenesis

Sterile20 (Ste20) 样激酶 MST4 在垂体肿瘤发生中的作用

基本信息

批准号：
9275374
负责人：
Margaret E Wierman
金额：
--
依托单位：
VA EASTERN COLORADO HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275374
关键词：
Adrenal hormone preparation Adverse effects Animal Model Automobile Driving Autopsy Biological Assay Blindness Brain Neoplasms Cell Death Cell Proliferation Cell model Cells Characteristics Clinical Colorado Computer Simulation Computers Data Databases Development Disease Erectile dysfunction Excision Frequencies Functional disorder Future Gene Amplification Genes Genetic Genetic Screening Genomic approach Genomics Goals Headache Health Care Costs Hormonal Human Hypopituitarism Hypoxia Impaired cognition Impotence Lead Libraries Light Malignant Neoplasms Measures Mediating Medical Molecular Mutation Nude Mice Null Lymphocytes Operative Surgical Procedures Oxidative Stress Pathogenesis Pathway interactions Patients Persons Phosphotransferases Physiology Pituitary Gland Pituitary Neoplasms Population Proteins Quality of life Radiation Radiation therapy Recurrence Residual state Risk Role Sampling Series Signal Transduction Site Somatotropin Sterility Stroke Structure System Tertiary Protein Structure Testing Testosterone Therapeutic Intervention Thyroid Hormones Transcript Translating Tumor Bank Tumor Subtype Universities Up-Regulation Veterans Vision Visual base clinical care cost design experimental study genetic approach genetic profiling genomic profiles germinal center kinases hormone deficiency in vivo inhibitor/antagonist kinase inhibitor member men mouse model neoplastic cell novel novel therapeutics overexpression pre-clinical public health relevance reproductive hormone response screening small molecule transcriptome treatment choice treatment strategy tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pituitary tumors are the most common brain tumor, found at autopsy in up to 20% of our population and clinically in 1/10,000 persons. With the current number of US veterans, this translates into over 225,000 veterans with pituitary tumors. Gonadotrope (or null cell) tumors occur more commonly in men who present clinically with erectile dysfunction, hormone deficiencies, headaches and visual disturbances progressing to blindness. Many of these tumors are invasive and recur. There are no available medical therapies for these large pituitary tumors and surgery remains the treatment of choice. The genetic and molecular mechanisms underlying pituitary tumorigenesis are poorly understood. We have amassed a unique bank of >300 human pituitary tumor and 100 normal pituitary samples tied to a clinical database. We performed a combined genetic screen to identify copy number alternations together with genomic transcriptome profiling using microarrays. Amplification of the MST4 gene, a Sterile 20-like germinal center kinase (GCK) III subfamily member was detected in an aggressive gonadotrope pituitary tumor together with increased MST4 transcript and protein levels in all pituitary tumors. Extensive new preliminary data demonstrate the role of MST4 driving proliferation and survival in response to oxidative stress and hypoxia to promote tumorigenesis. In this revised Merit Review we propose: Aim 1: To determine the frequency of altered copy number, translocation or mutation in the MST4 kinase as a mechanism contributing to human pituitary tumor pathogenesis. These experiments will define the mechanism of MST4 dysregulation in human pituitary tumors. Aim 2: To examine the importance of the kinase domain of MST4 to mediate its effects on proliferation and survival and confirm or refute the role of MST4 to mediate tumor growth in a preclinical mouse model. Studies using gonadotrope and growth hormone pituitary cells based systems will dissect the critical regions of MST4 to mediate tumorigenesis using read outs of proliferation, survival in response to oxidative stress or hypoxia and clonagenic assays. Results will be confirmed in a preclinical ex vivo nude mouse model to confirm the ability to MST4 to promote tumorigenesis in vivo. Aim 3: To identify small molecules with the capacity to inhibit MST4 activity and establish the structural characteristics necessary for selective MST4 inhibition. Library screening of known compounds together with in silico computer screening will identify known or design new candidate MST4 kinase inhibitors that will be tested in the cell and animal models as proof of concept for our ultimate goal of targeting MST4 in human pituitary tumors. Together these studies will use cutting edge genetic and genomic approaches together with mechanistic studies to dissect the role of dysregulation of MST4 in human pituitary tumors. These studies will shed light into the pathobiology of pituitary tumors. Targeting of the MST4 kinase may provide novel medical treatment strategies for our patients with pituitary tumors and other malignancies where MST4 is dysregulated.

描述（由申请人提供）：垂体瘤是最常见的脑肿瘤，在尸检中发现高达20%的人口和临床上在1/10，000人。以目前美国退伍军人的数量，这意味着超过225，000名退伍军人患有垂体瘤。促性腺激素（或空细胞）肿瘤更常见于临床表现为勃起功能障碍、激素缺乏、头痛和视力障碍进展为失明的男性。这些肿瘤中的许多是侵袭性的和复发的。对于这些大型垂体瘤没有可用的药物治疗，手术仍然是治疗的选择。垂体肿瘤发生的遗传和分子机制知之甚少。我们已经积累了一个独特的银行>300人垂体肿瘤和100正常垂体样本绑定到临床数据库。我们进行了一个组合的遗传筛选，以确定拷贝数的变化连同基因组转录谱使用微阵列。MST 4基因扩增，不育20-样生发中心激酶（GCK）III亚家族成员，检测到在一个积极的促性腺激素垂体瘤连同增加MST 4转录和蛋白水平在所有垂体瘤。广泛的新的初步数据表明，MST 4在响应氧化应激和缺氧以促进肿瘤发生中驱动增殖和存活的作用。在这个修订的优点审查，我们提出：目的1：确定的频率改变拷贝数，易位或突变的MST 4激酶作为一种机制，有助于人类垂体瘤的发病机制。这些实验将确定人类垂体瘤中MST 4失调的机制。目标二：在临床前小鼠模型中，研究MST 4激酶结构域介导其对增殖和存活的影响的重要性，并证实或反驳MST 4介导肿瘤生长的作用。使用促性腺激素和生长激素垂体细胞为基础的系统的研究将剖析MST 4的关键区域，以介导肿瘤发生，使用读出的增殖，生存在氧化应激或缺氧和克隆原性测定。将在临床前离体裸鼠模型中证实结果，以证实MST 4促进体内肿瘤发生的能力。目标三：鉴定具有抑制MST 4活性能力的小分子，并确定选择性MST 4抑制所需的结构特征。已知化合物的文库筛选以及计算机筛选将鉴定已知或设计新的候选MST 4激酶抑制剂，这些抑制剂将在细胞和动物模型中进行测试，作为我们靶向人类垂体肿瘤中MST 4的最终目标的概念证明。这些研究将使用尖端的遗传学和基因组学方法以及机制研究来剖析MST 4在人类垂体瘤中的失调作用。这些研究将阐明垂体瘤的病理生物学。靶向MST 4激酶可能为我们的垂体瘤和MST 4失调的其他恶性肿瘤患者提供新的药物治疗策略。