Stratifying the progression and prognosis of lung cancer subtypes with tumor supp

通过肿瘤支持对肺癌亚型的进展和预后进行分层

基本信息

批准号：
8089218
负责人：
Fulvio Bruno Lonardo
金额：
$ 16.03万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-14 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089218
关键词：
Accounting Address Adenocarcinoma Adverse effects Apoptosis Basic Science Biochemical Biological Blood Circulation Cancer Etiology Cell Line Clinical Clinical Research Complex Consensus Disease Drug Combinations Epidemiology Epigenetic Process Epithelial Equilibrium Evaluation Genetic Goals Histone Deacetylase Inhibitor Human In Vitro Large Cell Carcinoma Location Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Messenger RNA Microscopic Molecular Non-Small-Cell Lung Carcinoma Nuclear Pharmaceutical Preparations Phenotype Proteins Research Serine Proteinase Inhibitors Smoking Specimen Squamous cell carcinoma Structure of parenchyma of lung Testing Therapeutic Tumor Angiogenesis Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation angiogenesis base cancer cell gain of function human HDAC1 protein improved inhibitor/antagonist lung small cell carcinoma maspin member molecular marker mortality novel outcome forecast public health relevance research study tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): The grim prognosis of lung cancer, that has an overall 10-15% survival at 5 years, remains in the US the leading cause of cancer mortality, provides a compelling rationale for studying the molecular basis of this malignancy. Surmising the common, general association with smoking, lung cancers differ at the microscopic, anatomical, epidemiological and clinical level and harbor complex genetic and epigenetic alterations. The goal to develop a strategy to block the tumor progression and improve the prognosis of lung cancer can realistically be achieved only when the biological complexity of this disease is taken into account. To this end, identification and understanding of molecular markers that are mechanistically involved in tumor progression is needed. Our preliminary study suggests histological subtype-dependent distinct correlations between the expression and/or subcellular localization of tumor suppressive maspin with the progression and prognosis of non small cell lung carcinoma (NSCLC). Maspin is an epithelial specific member of the serine protease inhibitor (serpin) superfamily but recently identified as an endogenous inhibitor of histone deacetylase 1 (HDAC1). Based on our additional preliminary evidence, we propose to test the HYPOTHESIS that maspin may be a marker that stratifies the progression and prognosis of different subtypes of NSCLC. In Specific Aim 1, we will study human lung tissue specimens and determine how the expression level and/or subcellular localization of maspin stratify the progression and prognosis of different types of NSCLC. We will also determine how maspin mRNA of disseminated cancer cells in circulation may correlate with the progression and survival of different subtypes of NSCLC. In Specific Aim 2, we will perform in vitro experiments with a panel of representative cell lines to test the hypothesis that different NSCLC subtypes may undergo distinct sequences of maspin dysregulation, as a gain of function in tumor progression. Given that maspin acts as an endogenous HDAC1 inhibitor, these in vitro studies will focus on whether and how the level and/or subcellular location of maspin correlates with the de-differentiated phenotypes of different subtypes of NSCLC cells; whether the biological activities of maspin result, at least in part, from its inhibitory effect on HDAC1; and whether and how maspin predicts the tumor sensitivity to HDAC inhibitor-based combination drug treatments. It remains a challenge to block tumor progression by tumor suppressor genes or proteins, since up- regulation of tumor suppressors may be impossible, nonspecific, or associated with adverse side effects. Alternatively, results from this application will address the possibility that an effective personalized therapeutic strategy may be based on the status of differential expression of a tumor suppressor gene such as maspin. To our knowledge, this is the first systematic study employing balanced clinical and basic research approaches. The expected results are likely to provide a definitive and insightful conclusion regarding whether and how the level and/or subcellular localization of maspin in human specimens may guide personalized therapeutic strategies, and have a significant impact on reducing the high mortality of lung cancer. PUBLIC HEALTH RELEVANCE: The research hypothesis and scope of our application concern the evaluation and mechanistic study of maspin, a novel endogenous HDAC1 inhibitor, in the progression, dissemination, angiogenesis and prognosis of different histological subtypes of human non-small cell lung carcinoma.

描述（由申请人提供）：肺癌的严峻预后，在5年内总体10-15％的生存率仍然是癌症死亡率的主要原因，为研究这种恶性肿瘤的分子基础提供了令人信服的理由。克服了与吸烟的普通关系，肺癌在显微镜，解剖学，流行病学和临床水平上有所不同，并怀有复杂的遗传和表观遗传学改变。只有在考虑到该疾病的生物学复杂性时，才能实际实现制定阻断肿瘤进展并改善肺癌预后的策略的目标。为此，需要鉴定和理解与机械上参与肿瘤进展的分子标记物的识别和理解。我们的初步研究表明，肿瘤抑制性maspin的表达和/或亚细胞定位之间的组织学亚型依赖性相关性，非小细胞肺癌（NSCLC）的进展和预后。 Maspin是丝氨酸蛋白酶抑制剂（SERPIN）超家族的上皮特异性成员，但最近被鉴定为组蛋白脱乙酰基酶1（HDAC1）的内源性抑制剂。根据我们的其他初步证据，我们建议检验以下假设：Maspin可能是NSCLC不同亚型的进展和预后分层的标志物。在特定目标1中，我们将研究人类肺组织标本，并确定Maspin的表达水平和/或亚细胞定位如何分层不同类型的NSCLC的进展和预后。我们还将确定循环中传播癌细胞的Maspin mRNA如何与NSCLC不同亚型的进展和存活相关。在特定的目标2中，我们将使用一系列代表性细胞系进行体外实验，以测试以下假设：不同的NSCLC亚型可能会受到MASPIN失调的不同序列，这是肿瘤进展中功能的增加。鉴于Maspin充当内源性HDAC1抑制剂，这些体外研究将重点介绍Maspin的水平和/或亚细胞位置与NSCLC细胞不同亚型的脱节型表型的水平和/或亚细胞位置相关。 Maspin的生物活性是否至少部分是由于其对HDAC1的抑制作用而导致的； Maspin是否以及如何预测对基于HDAC抑制剂组合药物治疗的肿瘤敏感性。通过肿瘤抑制基因或蛋白质阻断肿瘤进展仍然是一个挑战，因为对肿瘤抑制剂的上调节可能是不可能的，非特异性的或与不良副作用相关的。另外，该应用程序的结果将解决有效的个性化治疗策略可能基于肿瘤抑制基因（如MASPIN）差异表达的状态的可能性。据我们所知，这是采用平衡临床和基础研究方法的第一个系统研究。预期的结果可能会为人类标本中MASPIN的水平和/或亚细胞定位提供明确而有见地的结论，可以指导个性化的治疗策略，并对降低肺癌的高死亡率产生重大影响。公共卫生相关性：我们应用的研究假设和范围涉及MASPIN的评估和机理研究，Maspin是一种新型的内源性HDAC1抑制剂，在人类非小细胞肺癌的不同组织学亚型的进展，传播，血管生成和预后。