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：
8811825
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/8811825
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 Gene Expression Profile Genes 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 Genetics 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 Reading 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 genetic approach genetic profiling 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 research study response screening small molecule 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）：垂体肿瘤是最常见的脑肿瘤，在尸检中最多有20％的人群，在1/10,000人中临床。由于目前的美国退伍军人人数，这转化为垂体肿瘤的225,000多名退伍军人。性腺（或无效细胞）肿瘤更常见于临床上勃起功能障碍，激素缺陷，头痛和视觉障碍发展为失明的男性。这些肿瘤中的许多是侵入性和复发性的。对于这些大型垂体肿瘤没有可用的医疗疗法，手术仍然是选择的治疗方法。垂体症状肿瘤发生的遗传和分子机制知之甚少。我们积累了一堆> 300个人类垂体肿瘤的独特库和与临床数据库相关的100个正常垂体样本。我们进行了一个组合的遗传筛选，以使用微阵列识别拷贝数交替以及基因组转录组分析。 MST4基因的扩增是在侵袭性的性腺垂体垂体肿瘤中检测到的无菌20种样生发中心激酶（GCK）III亚家族成员，以及所有垂体肿瘤中MST4转录物和蛋白质水平的增加。广泛的新初步数据证明了MST4驱动增殖和生存在响应氧化应激和缺氧以促进肿瘤发生的作用。在这项修订的优点审查中，我们提出：目标1：确定MST4激酶中拷贝数，转运或突变的频率，作为有助于人垂体肿瘤发病机理的机制。这些实验将定义人垂体肿瘤中MST4失调的机制。目的2：检查MST4激酶结构域对介导其对增殖和存活的影响的重要性，并确认或反驳MST4在临床前小鼠模型中介导肿瘤生长的作用。基于促性腺脱脂型和生长激素垂体细胞系统的研究将剖析MST4的关键区域，以使用增殖的读数，响应氧化应激或缺氧和可核测定法的响应，以介导肿瘤发生。结果将在临床前裸小鼠模型中得到确认，以确认MST4促进体内肿瘤发生的能力。目标3：鉴定具有抑制MST4活性能力的小分子并确定选择性MST4抑制所需的结构特征。库对已知化合物的库筛选以及在计算机计算机筛选中将识别已知或设计新的候选MST4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MST4的概念证明。这些研究将共同使用尖端遗传和基因组方法以及机械研究，以剖析MST4在人垂体肿瘤中的作用。这些研究将阐明垂体肿瘤的病理生物学。 MST4激酶的靶向可能为垂体肿瘤和其他MST4失调的恶性肿瘤患者提供新的医疗治疗策略。