Chemoprevention of pituitary gonadotrope tumors

描述（由申请人提供）：垂体腺瘤是所有垂体疾病中最常见的，在两性中均可见。患病率估计为每105人中约90例。大多数来自促性腺细胞谱系，这些肿瘤不分泌高糖蛋白激素[即黄体生成素（LH）和促卵泡激素（FSH）]，因此被称为无细胞腺瘤。临床表现包括神经系统症状，如脑组织损伤、视交叉、视力下降、颅内压升高、持续头痛和恶心。因为无细胞腺瘤没有明确的诊断标记，所以直到进展到非常严重的时候才会被发现，而手术是唯一的治疗方法。目前尚无针对零细胞腺瘤的模型系统或化学预防方案。我们已经开发了一种独特的转基因小鼠菌株，可发展促性腺激素富集的垂体腺瘤和表型人类垂体无细胞腺瘤，包括。我们的长期目标是了解零细胞腺瘤的起源和发展机制，并制定新的化学预防策略。本提案的目的是确定促性腺激素肿瘤进展的生物标志物和特定靶点/途径，从而最终获得人类零细胞腺瘤进展和预防的机制见解。我们的中心假设是雌激素受体-1 （ESR1）和印度刺猬（IHH）都有助于垂体促性腺腺瘤的生长，抑制它们的表达可以带来临床益处。在特异性目标1中，我们将确定雌激素信号影响肿瘤生长和进展的机制。雌激素对糖基化的影响导致激素分泌失败

DESCRIPTION (provided by applicant): Pituitary adenomas are the most frequent of all pituitary diseases and are observed in both sexes. The prevalence is estimated as ~90 cases per 105 people. The majority arises from the gonadotrope lineage and these tumors do not hypersecrete glycoprotein hormones [i.e., luteinizing hormone (LH) and follicle stimulating hormone (FSH)] and thus are called null cell adenomas. The clinical manifestations include neurological symptoms such as damage to brain tissue and optic chiasm, vision loss, increased intracranial pressure, persistent headache and nausea. Because they have no well-defined diagnostic markers, null cell adenomas often go undetected until they are very advanced and surgery is the only treatment. There are no established model systems or chemoprevention options available for null cell adenomas. We have developed a unique transgenic strain of mice that develops gonadotrope-enriched pituitary adenomas and phenocopies human pituitary null cell adenomas including. Our long-term goal is to understand the mechanisms of origin and progression of null cell adenoma, and develop new strategies of chemoprevention for it. The objective of this proposal is to identify biomarkers and specific targets/pathways responsible for gonadotrope tumor progression such that mechanistic insights into progression and prevention of human null cell adenomas could ultimately be obtained. Our central hypothesis is that both estrogen receptor-1 (ESR1) and Indian hedgehog (IHH) contribute to growth of pituitary gonadotrope adenomas and inhibiting their expression leads to clinical benefit. In Specific Aim 1, we will determine the mechanism by which estrogen signaling influences tumor growth and progression. Effects of estrogen on glycosylation that contribute to hormone secretion failure will be evaluated. Additionally, a novel mouse model in which gonadotrope tumors are fluorescently labeled will be used to identify potential biomarkers. In Specific Aim 2, we will test the efficacyof anti-estrogen therapy to regulate gonadotrope tumor growth. The approach involves the use of mice conditionally overexpressing Esr1 at desired times, and mice lacking either Esr1 or Esr2 on the tumor-prone transgenic background. The in vivo tumor preventive effects of tamoxifen will also be tested. In Specific Aim 3, we will determine the effects of blocking IHH action on gonadotrope tumor development. We will specifically delete Ihh in gonadotrope tumors by using a cre-lox approach. In a second approach, the effects of hedgehog chemoprevention agents will be tested in gonadotrope tumors of transgenic mice. The approach is innovative, because it utilizes a unique transgenic mouse model that develops gonadotrope tumors and uses a combination of in vitro and novel in vivo models. The proposed research is significant because it is expected to vertically advance and expand understanding of how chemopreventive agents targeted to block estrogen and hedgehog signaling regulate gonadotrope/null cell adenomas.