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

描述（由申请人提供）：肺癌的预后恶劣，5年生存率为10-15%，在美国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。推测吸烟与肺癌的共同、普遍关联在显微镜、解剖学、流行病学和临床水平上存在差异，并且存在复杂的遗传和表观遗传改变。只有考虑到这种疾病的生物学复杂性，才能真正实现制定阻断肿瘤进展和改善肺癌预后的策略。为此，需要鉴定和了解在机制上参与肿瘤进展的分子标记。我们的初步研究表明，肿瘤抑制蛋白的表达和/或亚细胞定位与非小细胞肺癌（NSCLC）的进展和预后之间存在组织学亚型依赖的明显相关性。Maspin是丝氨酸蛋白酶抑制剂（serpin）超家族的上皮特异性成员，但最近被发现是一种内源性组蛋白去乙酰化酶1 （HDAC1）抑制剂。基于我们额外的初步证据，我们提出验证maspin可能是区分不同NSCLC亚型的进展和预后的标志物的假设。在Specific Aim 1中，我们将研究人肺组织标本，并确定maspin的表达水平和/或亚细胞定位如何对不同类型NSCLC的进展和预后进行分层。我们还将确定循环中弥散性癌细胞的maspin mRNA如何与不同亚型NSCLC的进展和存活相关。在Specific Aim 2中，我们将使用一组具有代表性的细胞系进行体外实验，以验证不同的NSCLC亚型可能经历不同序列的masmasin失调，作为肿瘤进展中的功能增益。鉴于maspin作为内源性HDAC1抑制剂，这些体外研究将关注maspin的水平和/或亚细胞位置是否以及如何与不同亚型NSCLC细胞的去分化表型相关；maspin的生物活性是否至少部分源于其对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阻断肿瘤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，或与不良副作用相关。另外，该应用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）的差异表达状态的可能性。据我们所知，这是第一个采用平衡的临床和基础研究方法的系统研究。预期的结果可能会提供一个明确的和有洞察力的结论，关于人类标本中巨噬蛋白的水平和/或亚细胞定位是否以及如何指导个性化治疗策略，并对降低肺癌的高死亡率产生重大影响。

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.