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

描述(申请人提供)：肺癌的严峻预后，5年内总体存活率为10%-15%，在美国仍然是癌症死亡的主要原因，这为研究这种恶性肿瘤的分子基础提供了令人信服的理由。推测与吸烟的普遍联系，肺癌在显微镜、解剖学、流行病学和临床水平上有所不同，并且存在复杂的遗传和表观遗传学变化。只有考虑到肺癌的生物学复杂性，才能真正实现阻断肿瘤进展和改善肺癌预后的策略。为此，需要鉴定和了解与肿瘤进展密切相关的分子标志物。我们的初步研究表明，肿瘤抑制蛋白maspin的表达和/或亚细胞定位与非小细胞肺癌(NSCLC)的进展和预后存在明显的组织亚型相关性。Maspin是丝氨酸蛋白酶抑制物(Serpin)超家族中上皮特异性的成员，但最近被发现是组蛋白脱乙酰基酶1(HDAC1)的内源性抑制物。基于我们额外的初步证据，我们建议检验maspin可能是不同亚型NSCLC进展和预后分层的标记物的假设。在具体目标1中，我们将研究人肺组织标本，并确定maspin的表达水平和/或亚细胞定位如何分层影响不同类型NSCLC的进展和预后。我们还将确定循环中播散性癌细胞的maspin mRNA如何与不同亚型的非小细胞肺癌的进展和生存相关。在特定的目标2中，我们将对一组有代表性的细胞系进行体外实验，以检验不同的NSCLC亚型可能经历不同的maspin失调序列的假设，作为在肿瘤进展中功能的获得。鉴于maspin作为内源性HDAC1抑制剂的作用，这些体外研究将集中于maspin的水平和/或亚细胞定位是否以及如何与不同亚型NSCLC细胞的去分化表型相关；maspin的生物学活性是否至少部分地源于其对HDAC1的抑制作用；以及maspin是否以及如何预测肿瘤对基于HDAC抑制剂的联合药物治疗的敏感性。通过肿瘤抑制基因或蛋白来阻断肿瘤的进展仍然是一个挑战，因为肿瘤抑制基因的上调可能是不可能的、非特异性的，或者与不良副作用相关。或者，这项应用的结果将解决这样一种可能性，即有效的个性化治疗策略可能基于肿瘤抑制基因(如maspin)的差异表达状态。据我们所知，这是第一次采用平衡的临床和基础研究方法的系统研究。对于maspin在人体标本中的水平和/或亚细胞定位是否以及如何指导个体化治疗策略，并对降低肺癌的高死亡率产生重大影响，预期的结果可能会提供一个明确和有洞察力的结论。 公共卫生相关性：我们的研究假设和应用范围涉及新型内源性HDAC1抑制剂Maspin在不同组织亚型人类非小细胞肺癌的进展、扩散、血管生成和预后中的评估和机制研究。

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.