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.
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.
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|Lonardo, Fulvio; Guan, Hui; Dzinic, Sijana et al. (2014) Maspin expression patterns differ in the invasive versus lepidic growth pattern of pulmonary adenocarcinoma. Histopathology 65:757-63|
|Dzinic, Sijana H; Kaplun, Alexander; Li, Xiaohua et al. (2013) Identification of an intrinsic determinant critical for maspin subcellular localization and function. PLoS One 8:e74502|
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