TARGETING HISTONE DEACETYLASES IN NSCLC

靶向 NSCLC 中的组蛋白脱乙酰酶

• 批准号: 7316646
• 负责人: PRAN K DATTA
• 金额: $ 21.73万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316646
• 关键词: A549; Acetylation; Affinity; Antineoplastic Agents; Apoptosis; Biological Assay; Biological Markers; Cancer cell line; Carbon; Carcinoma in Situ; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Markers; Clinical Trials; Complex; Cyclin D1; DNA; Data; Disease regression; Disseminated Malignant Neoplasm; Dose; Down-Regulation; E-Cadherin; Electrophoretic Mobility Shift Assay; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelium; Genes; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Histone H3; Histone deacetylase inhibition; Histones; Human; Hydroxyprostaglandin Dehydrogenases; Hypermethylation; Immunohistochemistry; In Situ; In Situ Nick-End Labeling; Intervention; Invasive; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Molecular; Molecular Profiling; Mutation; Non-Small-Cell Lung Carcinoma; Nude Mice; Numbers; Oligonucleotides; Outcome; Pathway interactions; Patient Selection; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phase II Clinical Trials; Phosphorylation; Play; Precipitation; Principal Investigator; Process; Protein Overexpression; Proteins; Proteomics; Resectable; Resistance; Response Elements; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Specimen; Standards of Weights and Measures; Surrogate Markers; Testing; Therapeutic Intervention; Thinking; Transferase; Tumor Promoters; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Vorinostat; Xenograft procedure; base; c-myc Genes; cancer cell; chromatin immunoprecipitation; inhibitor/antagonist; insight; leukemia; neoplastic cell; novel; promoter; protein expression; research study; response; restoration; therapeutic target; transcription factor; tumor

This project is based on the hypothesis that histone deacetylation is a crucial step in the loss of specific homeostatic molecular signals in the transition from normal lung epithelium to in situ carcinoma, and finally to invasive and metastatic lung cancer. Loss of TGF-G-induced tumor suppressor function in tumors is one such signal, and resistance to TGF-& in lung cancers occurs mostly through the loss of TISRII expression. Our experiments suggest that activation of the MAPK/ERK pathway causes down-regulation of TURN through histone deacetylation and further that DNA hypermethylation has no effect. In addition, we have observed that TGF-li-induced tumor suppressor function is restored in TGF-li resistant lung cancer cells via exogenous TBRII expression or with the treatment of histone deacetylase (HDAC) inhibitors (HDI). The expression of other tumor suppressor genes including PGDH, E-cadherin and p21cl" is also reduced in lung cancer cell lines due to histone deacetylation. HDAC inhibitors are exciting new anticancer agents that inhibit proliferation, and induce apoptosis and differentiation of tumor cells. Clinical trials of the HDI SAHA show that this inhibitor is well tolerated at the doses required to hyperacetylate histones and show clinical potential for the treatment of leukemias and solid tumors. We will study the clinical and molecular effects of SAHA in Phase II clinical trials in patients with advanced or resectable non-small cell lung cancer. We have hypothesized that since the majority of lung tumors are resistant to TGF-S due to loss of TBRII, restoration of TGF-IJ signaling by SAHA (in addition to its other antitumor effects) may be an effective therapeutic intervention alone or in combination with other agents in lung cancer. The overall goals of this project are 1) to determine the mechanism by which lung tumors become resistant to TGF-B tumor suppressor function, 2) to determine a molecular profile that can identify candidate patients who are more likely to respond to SAHA, and 3) to identify novel surrogate clinical markers of drug-induced inhibition of HDAC activity that will give insights into the mechanisms of SAHA antitumor activity or resistance. The following Specific Aims are proposed: (1) To determine the mechanism for the loss of TGF-6-induced tumor suppressor function. (2) To determine the intracellular signaling pathways involved in the down-regulation of TIJRII and PGDH in primary lung cancer. (3) To determine whether restoration of TGF-IJ signaling by the HDI, SAHA can be a potential mechanism for its antitumor activity. (4) To determine if SAHA inhibits HDAC activity in patients and to test candidate molecular profiles predictive of clinical benefit from SAHA.

这个项目是基于这样的假设，即组蛋白去乙酰化是一个关键的步骤，在特定的损失， 从正常肺上皮到原位癌，最后到 侵袭性和转移性肺癌。肿瘤中TGF-β诱导的肿瘤抑制功能的丧失就是其中之一。 肺癌中对TGF-β的抗性主要通过TISRII表达的丧失而发生。我们 实验表明MAPK/ERK通路的激活通过以下途径引起TURN的下调： 组蛋白去乙酰化和进一步DNA超甲基化没有影响。此外，我们还观察到， TGF-11诱导的肿瘤抑制功能在TGF-11抗性肺癌细胞中通过外源性的免疫抑制剂而恢复。 TBRII表达或用组蛋白脱乙酰酶（HDAC）抑制剂（HDI）治疗。的表达 其它肿瘤抑制基因包括PGDH、E-cadherin和p21 cl-在肺癌细胞系中也减少 由于组蛋白脱乙酰化。HDAC抑制剂是令人兴奋的抑制增殖的新型抗癌剂， 诱导肿瘤细胞凋亡和分化。HDI SAHA的临床试验表明，这种抑制剂 在高乙酰化组蛋白所需的剂量下耐受良好，并显示出治疗 白血病和实体瘤。我们将在II期临床试验中研究SAHA的临床和分子效应 晚期或可切除的非小细胞肺癌患者。我们假设自从 大多数肺肿瘤由于TBRII的丧失、SAHA恢复TGF-IJ信号传导（在肺肿瘤中）而对TGF-S具有抗性。 除了它的其它抗肿瘤作用之外）可以是单独或组合的有效治疗干预 与其他药物一起治疗肺癌。本项目的总体目标是：1）通过以下方式确定机制： 肺肿瘤对TGF-β肿瘤抑制功能产生耐药性，2）确定分子特征 可以识别更有可能对SAHA有反应的候选患者，以及3）识别新的 药物诱导的HDAC活性抑制的替代临床标志物， SAHA抗肿瘤活性或抗性的机制。具体目标如下：（1） 确定TGF-6诱导的肿瘤抑制功能丧失的机制。(2)确定 参与原发性肺癌中TIJRII和PGDH下调的细胞内信号通路。 (3)为了确定HDI是否恢复TGF-β 1信号传导，SAHA可能是一种潜在的机制， 其抗肿瘤活性。(4)确定SAHA是否抑制患者的HDAC活性，并测试候选药物 预测SAHA临床获益的分子谱。