Endocrine Targets for Prevention of Lung Cancer

描述（由申请人提供）：拟议研究的总体目标是确定基于内分泌的肺癌预防和/或治疗治疗的靶点。流行病学数据表明，非小细胞肺癌存在性别差异，卵巢激素通过促进肿瘤生长发挥作用，特别是在腺癌中。激素的肿瘤促进作用可能在癌变过程的早期最为有效。因此，旨在开发基于内分泌的化学预防措施的研究最好是在受控的、可诱导的动物模型中进行研究。我们利用一种独特的基于致癌性KRAS （KRasG12D）条件表达和Tp53同时缺失的肺腺癌小鼠模型，发现女性比男性发生更多的肿瘤和更高级别的肿瘤。卵巢切除术消除了这些性别差异，雌激素治疗恢复了肿瘤数量，但没有肿瘤分级，表明另一个卵巢因素参与了肿瘤的进展。考虑到雌激素和黄体酮在其他器官癌症中的相互作用，黄体酮可能是卵巢肿瘤进展因子。因此，卵巢类固醇受体是合理的干预目标。已知雌激素有三种受体蛋白，核配体激活转录因子，ER？呃?和膜g蛋白偶联受体GPER。肺细胞表达所有三种雌激素受体；它们也表达黄体酮受体（PR），另一种核配体激活的转录因子。我们的初步观察表明，广泛使用的抗雌激素，他莫昔芬和氟维司汀，作为激动剂，促进小鼠肺癌模型的肿瘤发生；这两种抗雌激素与所有三种受体相互作用，产生激动剂或拮抗剂作用，这取决于所检查的组织和生理过程。因此，在设计靶向治疗之前，有必要明确雌激素促进肺肿瘤的途径。使用在其他器官系统中证明有效的三种受体特异性化合物，我们将确定三种雌激素受体类型中哪一种介导雌激素的肿瘤启动子作用。通过这种方式，我们可以确定未来开发抗雌激素的精确靶点，用于治疗肺癌。另一方面，使用抗黄体酮，米非司酮，我们将确定PR在肿瘤进展中的作用。除了评估治疗对肿瘤发生的影响外，我们还将检查与该过程相关的中间终点。我们将确定肿瘤前细胞的细胞增殖和凋亡率，我们将评估几种已知的通过不同分子途径对雌激素有反应的基因的表达。通过这种方式，我们将把治疗对肿瘤发生和导致肿瘤发展的细胞过程的影响联系起来。这些小规模的研究将为测试受体特异性雌激素拮抗剂和其他pr特异性拮抗剂在预防肺部肿瘤生长和进展方面的作用铺平道路。

DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to define targets for endocrine based preventative and/or therapeutic treatments in lung cancer. Epidemiological data indicate that there are sex differences in non-small cell lung cancer and that ovarian hormones play a role by promoting tumor growth, particularly in adenocarcinoma. Tumor promoter action of hormones is likely to be most effective early in the carcinogenic process. For that reason, studies aimed at development of endocrine-based chemopreventive measures are best studied in controlled, inducible animal models. Using a unique murine model of lung adenocarcinoma based on the conditional expression of oncogenic KRAS (KRasG12D) and concurrent deletion of Tp53, we have found that females develop more tumors and higher grade tumors than males. Ovariectomy abrogates these sex differences and estrogen treatment restores tumor number but not tumor grade, indicating that another ovarian factor is involved in tumor progression. Considering the interplay between estrogen and progesterone in cancers of other organs, it is likely that progesterone is the ovarian tumor progression factor. Thus, receptors for ovarian steroids are logical targets for intervention. There are three known receptor proteins for estrogen, the nuclear ligand-activated transcription factors, ER? and ER?, and the membrane G-protein coupled receptor, GPER. Lung cells express all three of the estrogen receptors; they also express progesterone receptor (PR), another nuclear, ligand activated transcription factor. Our preliminary observations indicate that the widely used antiestrogens, tamoxifen and fulvestrant, behave as agonists, promoting tumorigenesis in the mouse lung cancer model; these two antiestrogens interact with all three receptor types, producing either agonist or antagonist action, depending on the tissue and the physiological process being examined. Hence, it is necessary to define the pathway(s) involved in estrogen promotion of lung tumors before designing targeted therapies. Using three receptor specific compounds proven effective in other organs systems, we will determine which of the three estrogen receptor types mediate the tumor promoter action of estrogens. In this way we can identify the precise target(s) for future development of antiestrogens that can be used against lung cancer. On the other hand, using the antiprogestin, mifepristone, we will determine the role of PR in tumor progression. In addition to assessing the effects of treatments on tumorigenesis, we will examine intermediate end points relevant to the process. We will determine the rate of cell proliferation and apoptosis in preneoplastic cells and we will assess expression of several genes known to be responsive to estrogens through distinct molecular pathways. In this way we will correlate the effect of treatment on tumorigenesis and cellular processes that lead to tumor development. These minimal studies will pave the way for testing receptor specific estrogen antagonists and additional PR-specific antagonists in prevention of tumor growth and progression in the lung. PUBLIC HEALTH RELEVANCE: Lung cancer differs between men and women, most likely due to the effects of ovarian hormones. Definition of the basic mechanisms involved in establishing sex differences in lung cancer is a prerequisite to rational design of novel endocrine-based preventative measures and/or therapies.