Changes in Tumor DNA Methylation with Decitabine

地西他滨对肿瘤 DNA 甲基化的影响

• 批准号: 7140143
• 负责人: DAVID J STEWART
• 金额: $ 26.37万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-02 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140143
• 关键词: DNA methylation; apoptosis; azo compounds; biopsy; blood tests; clinical research; clinical trial phase I; deoxycytidine; dosage; drug adverse effect; drug resistance; drug screening /evaluation; gene expression; gene induction /repression; human subject; human therapy evaluation; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; patient oriented research; pharmacokinetics; polymerase chain reaction; sulfites; tumor suppressor genes

DESCRIPTION (provided by applicant): Impact of the new drug decitabine on human tumor DNA methylation will be assessed. Down-regulation of tumor suppressor genes & pro-apoptotic genes needed for chemotherapy efficacy may occur due to DNA hypermethylation. Decitabine may decrease DNA methylation & up-regulate gene expression at doses well below maximum tolerated dose (MTD), & effect may plateau at low doses. Six patients treated at each of 5 decitabine dose levels (2.5-20 mg/m2/day days 1-5 & 8-12 of a cycle) in a phase I trial will have tumor biopsies pre & post decitabine. Aim 1: To assess decitabine-induced changes in global DNA methylation, using ALU & LINE assays to compare pre- vs. post-decitabine tumor specimens, and to determine: a) if the effect on DNA methylation is linear at low doses but plateaus as decitabine dose increases; b) the dose at which any such plateau occurs. In later studies (beyond the scope of this grant) in more homogeneous patient populations we will assess if this plateau-level dose is as effective as the MTD: a) in single agent activity vs. specific cancers; b) at reversing resistance to other agents; and c) at demethylating and upregulating expression of silenced tumor suppressor & pro-apoptotic genes. Aim 2: To correlate changes in tumor with changes in peripheral blood mononuclear cell (PBMC) DNA methylation with decitabine. If decitabine impact on PBMC DNA methylation mirrors its impact on tumor DNA methylation, then PBMCs may serve as a useful surrogate for tumor DNA methylation. Aim 3: To use pyrosequencing to conduct preliminary proof-of-principle assessments of impact of decitabine on methylation of selected tumor-suppressor & pro-apoptotic genes. For individual tumors, we will preferentially assess genes frequently reported to be silenced by hypermethylation in that specific tumor type. Impact on individual genes will be confirmed in later studies (beyond the scope of this grant). This preliminary look at individual genes may provide a molecular rationale for future decitabine therapeutic studies in specific relevant tumor types.

描述（由申请人提供）：将评估新药地西他滨对人类肿瘤 DNA 甲基化的影响。 DNA 高甲基化可能会导致化疗效果所需的抑癌基因和促凋亡基因下调。地西他滨在远低于最大耐受剂量 (MTD) 的剂量下可能会降低 DNA 甲基化并上调基因表达，并且在低剂量时效果可能会趋于稳定。在 I 期试验中，以 5 种地西他滨剂量水平（2.5-20 mg/m2/天，周期的第 1-5 和 8-12 天）治疗的 6 名患者将在地西他滨前后进行肿瘤活检。目标 1：评估地西他滨诱导的整体 DNA 甲基化变化，使用 ALU 和 LINE 检测比较地西他滨治疗前与治疗后的肿瘤样本，并确定：a) 在低剂量但稳定状态下，对 DNA 甲基化的影响是否呈线性随着地西他滨剂量的增加； b) 出现任何此类平台的剂量。在以后的研究中（超出了本次资助的范围），我们将在更同质的患者群体中评估这种平台水平剂量是否与 MTD 一样有效： b) 逆转对其他药物的耐药性； c) 去甲基化和上调沉默的肿瘤抑制基因和促凋亡基因的表达。目标 2：将地西他滨导致的肿瘤变化与外周血单核细胞 (PBMC) DNA 甲基化的变化联系起来。如果地西他滨对 PBMC DNA 甲基化的影响反映了其对肿瘤 ​​DNA 甲基化的影响，那么 PBMC 可能作为肿瘤 DNA 甲基化的有用替代品。目标 3：使用焦磷酸测序对地西他滨对选定肿瘤抑制基因和促凋亡基因甲基化的影响进行初步原理验证评估。对于个体肿瘤，我们将优先评估在该特定肿瘤类型中经常被报告因高甲基化而沉默的基因。对个体基因的影响将在以后的研究中得到证实（超出了本次资助的范围）。对单个基因的初步研究可能为未来特定相关肿瘤类型的地西他滨治疗研究提供分子原理。