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.

该项目基于以下假设：组蛋白脱乙酰化是特定损失的关键步骤 从正常肺上皮到原位癌的过渡中的稳态分子信号，最后 侵入性和转移性肺癌。肿瘤中TGF-G诱导的肿瘤抑制功能的丧失就是这样一种 信号，对TGF-和肺癌中的抗性主要是由于Tisrii表达的丧失而发生。我们的 实验表明，MAPK/ERK途径的激活导致转弯的下调 组蛋白脱乙酰基化，进一步表明DNA高甲基化没有作用。另外，我们已经观察到 TGF-LI诱导的肿瘤抑制功能通过外源性在TGF-LI抗性肺癌细胞中恢复 TBRII表达或组蛋白脱乙酰基酶（HDAC）抑制剂（HDI）的处理。表达 肺癌细胞系中的其他肿瘤抑制基因也包括PGDH，E-钙粘着蛋白和P21CL” 由于组蛋白脱乙酰化。 HDAC抑制剂是令人兴奋的新抗癌剂，抑制增殖，并且 诱导肿瘤细胞的细胞凋亡和分化。 HDI SAHA的临床试验表明，该抑制剂是 以高乙酰化组蛋白所需的剂量耐受性，并显示出治疗的临床潜力 白血病和实体瘤。我们将研究SAHA在II期临床试验中的临床和分子作用 患有晚期或可切除的非小细胞肺癌的患者。我们假设以来 由于TBRII的丧失，SAHA恢复TGF-JIJ信号，大多数肺肿瘤对TGF-S有抵抗力（在 除其他抗肿瘤效果）可能单独或组合是有效的治疗干预措施 与肺癌中的其他药物。该项目的总体目标是1）确定机制 哪些肺肿瘤对TGF-B肿瘤抑制剂功能具有抗性，2）确定分子剖面 可以识别更有可能对Saha做出反应的候选患者，以及3）确定新颖的患者 药物诱导的HDAC活性抑制的替代临床标志物将为您提供见解 SAHA抗肿瘤活性或抗性的机制。提出了以下特定目标：（1） 确定TGF-6诱导的肿瘤抑制功能丧失的机制。 （2）确定 原发性肺癌中tijrii和PGDH的下调涉及细胞内信号通路。 （3）确定HDI是否恢复TGF-IJ信号传导，SAHA可以成为潜在的机制 它的抗肿瘤活性。 （4）确定SAHA是否抑制患者的HDAC活性并测试候选者 SAHA的临床益处可预测分子特征。