The Role of Selective HDAC Enzymes in Drug Sensitivity

选择性 HDAC 酶在药物敏感性中的作用

• 批准号: 7674687
• 负责人: Pamela N. Munster
• 金额: $ 27.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-18 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674687
• 关键词: Aftercare; Antineoplastic Agents; Apoptosis; Biological; Biological Process; Biological Products; Breast Cancer Treatment; Cell Culture Techniques; Cell Cycle Arrest; Cell Cycle Regulation; Cells; Chromatin; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cytotoxic agent; DNA; DNA Damage; Data; Development; Dose; Down-Regulation; Drug Exposure; Enzymes; Epirubicin; Exposure to; Family member; Future; Growth; HDAC1 gene; HDAC2 gene; HDAC6 gene; Half-Life; Heterochromatin; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Hour; In Vitro; Individual; Mediating; Modeling; Organ; Organ Specificity; Patient Selection; Patients; Pattern; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physical condensation; Play; Proteins; Reporting; Research Personnel; Role; Sampling; Small Interfering RNA; Somatic Cell; Staging; System; Testing; Tissues; Topoisomerase; Topoisomerase Inhibitors; Topoisomerase-II Inhibitor; Toxic effect; Tumor Tissue; Variant; Work; cancer cell; cell transformation; cellular targeting; chemotherapy; chromatin remodeling; cytotoxic; design; drug sensitivity; improved; in vitro Model; malignant breast neoplasm; neoplastic cell; next generation; pre-clinical; programs; response; therapeutic target; treatment effect; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Histone deacetylase (HDAC) enzymes play an important part in the development and progression of cancer and HDAC inhibitors (HDACi) are currently being tested as anti-cancer agents. Early clinical trials show that these drugs have anti-tumor activity, but the response rates are low and it is unclear which patients may benefit from HDACi. There are at least 17 HDAC family members, yet very little is known about the function of individual HDACs and their relevance as specific therapeutic targets. It has been shown that HDACi cause cell cycle arrest and differentiation in cancer cells. HDACi further promote chromatin decondensation and potentiate DMA damage induced by cytotoxic agents (such as topoisomerase (topo) inhibitors). However, the effects of HDACi on tumor tissues are dependent on the dose and duration of drug treatment and the effects vary greatly between different tumor types. We hypothesized that the effects of HDACi such as chromatin decondensation, growth inhibition and sensitization to chemotherapy may not only depend on the inhibition of specific HDAC enzymes, but is also determined by the expression of specific HDAC enzymes in the target tissue. This is supported by our preliminary data showing that mainly HDAC2 was involved in chromatin de- condensation. We found that the inhibition of HDAC2 by selective siRNA depletion was sufficient to cause chromatin decondensation. Furthermore, neither HDACi-induced chromatin decondensation nor sensitization to topo inhibitors was seen in cells lacking HDAC2. In contrast, while not associated with chromatin decondensation, HDAC6 was involved in cell cycle regulation and may determine the phase of the cell cycle arrest. These findings suggest that defining the roles of individual HDAC enzymes as specific therapeutic targets could vastly improve the next generation of HDACi, the selection of patients, and the optimal design of clinical trials for these drugs either alone or in combination. In Specific Aim 1, we will therefore define the roles of specific HDAC enzymes as therapeutic targets and the consequence of their selective inhibition in cell culture models by the depletion of specific HDACs using siRNA and in cell systems with variant HDAC expression. In Specific Aim 2, patients with early stage breast cancer will be treated with an HDACi, prior to exposure to a topo II inhibitor. In pre- and post-treatment tumor samples, we will determine which HDACs are involved in the cellular effects induced by the HDACi and which HDACs may predict response.

描述（由申请人提供）：组蛋白脱乙酰酶（HDAC）在癌症的发生和进展中发挥重要作用，HDAC抑制剂（HDACi）目前正在作为抗癌药物进行测试。早期临床试验表明这些药物具有抗肿瘤活性，但缓解率较低，尚不清楚哪些患者可能从 HDACi 中受益。 HDAC 家族至少有 17 个成员，但人们对各个 HDAC 的功能及其作为特定治疗靶点的相关性知之甚少。研究表明，HDACi 会导致癌细胞的细胞周期停滞和分化。 HDACi 进一步促进染色质解缩并增强细胞毒性药物（例如拓扑异构酶 (topo) 抑制剂）诱导的 DMA 损伤。然而，HDACi对肿瘤组织的作用取决于药物治疗的剂量和持续时间，并且不同肿瘤类型之间的作用差异很大。我们推测HDACi的染色质解缩、生长抑制和化疗敏感性等作用可能不仅取决于特定HDAC酶的抑制，而且还取决于靶组织中特定HDAC酶的表达。我们的初步数据支持了这一点，显示主要是 HDAC2 参与染色质解浓缩。我们发现选择性 siRNA 消耗对 HDAC2 的抑制足以引起染色质解浓缩。此外，在缺乏 HDAC2 的细胞中，未观察到 HDACi 诱导的染色质解缩和对拓扑抑制剂的敏感性。相比之下，虽然与染色质解缩无关，但 HDAC6 参与细胞周期调节，并可能决定细胞周期停滞的阶段。这些发现表明，将单个 HDAC 酶的作用定义为特定的治疗靶点可以极大地改善下一代 HDACi、患者的选择以及这些药物单独或组合的临床试验的最佳设计。因此，在具体目标 1 中，我们将定义特定 HDAC 酶作为治疗靶标的作用，以及它们在细胞培养模型中通过使用 siRNA 消耗特定 HDAC 以及在具有变异 HDAC 表达的细胞系统中选择性抑制的结果。在具体目标 2 中，早期乳腺癌患者将在接受拓扑 II 抑制剂治疗之前接受 HDACi 治疗。在治疗前和治疗后的肿瘤样本中，我们将确定哪些 HDAC 参与了 HDACi 诱导的细胞效应，以及哪些 HDAC 可以预测反应。