Pre-operative Decitabine in Colon Cancer: a Proof of Principle Study
试验速览
- 阶段
- 不适用
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Wnt target gene expression (APCDD1, AXIN2, DKK1, LGR5 and ASCL2)
研究概览
简要总结
Background of the study: Colon cancer is the second leading cause of cancer-related death world wide.
Although patients presenting with early disease (stage I-III) can be cured, prognosis varies from 90% in stage I to 50-80% in stage II and III. Therefore, prevention of metastases after early disease is of utmost importance. Derepression of Wnt targets may provide a novel target for therapy.
Objectives: The primary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can increase Wnt target gene expression as measured in resected tumors compared to pretreatment biopsies. The secondary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can revert CpG methylation and induce more favorable tumor characteristics as measured in resected tumors compared to pretreatment biopsies. The tertiary objective is to compare changes in Wnt target gene expression, CpG methylation and tumor characteristics for Wnt methylated and nonmethylated tumors as measured in resected tumors compared to pretreatment biopsies and identify new stratification markers.
详细描述
Rationale: Colon cancer is the second leading cause of cancer-related death world wide.
Although patients presenting with early disease (stage I-III) can be cured, prognosis varies from 90% in stage I to 50-80% in stage II and III. Therefore, prevention of metastases after early disease is of utmost importance. Extensive studies of the Wnt signal cascade have elucidated its role in colorectal cancer development and proliferation. Several well-known targets of the Wnt-cascade, like DKK1, APCDD1 and AXIN2, serve as feedback inhibitors and likely prevent pathway hyperactivation. Therefore, loss of these control mechanisms, for example due to repression of Wnt targets by CpG island methylation, serves as a potent proliferative signal. Recently, we identified a subset of colon cancers that are typified by CpG island methylation of specific Wnt target genes and have a poor prognosis. Moreover, in preclinical studies we showed that derepression of Wnt-targets by the demethylating agent decitabine resulted in tumor growth suppression. Thus, derepression of Wnt targets may provide a novel target for therapy. Objectives: The primary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can increase Wnt target gene expression as measured in resected tumors compared to pretreatment biopsies. The secondary objective of the study is to assess in patients with primary colon cancer whether short-course pre-operative treatment with decitabine can revert CpG methylation and induce more favorable tumor characteristics as measured in resected tumors compared to pretreatment biopsies. The tertiary objective is to compare changes in Wnt target gene expression, CpG methylation and tumor characteristics for Wnt methylated and nonmethylated tumors as measured in resected tumors compared to pretreatment biopsies and identify new stratification markers.
Study design: Interventional study.
Study population:
Patients > 18 yr old with histopathologically proven or high suspicion of colon cancer.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Decitabine treatment
Treatment with decitabine
干预措施: Decitabine (Drug)
结局指标
主要结局
Wnt target gene expression (APCDD1, AXIN2, DKK1, LGR5 and ASCL2)
时间窗: 30 minutes after surgery
The primary objective of the study is to assess whether short-course pre-operative treatment with the demethylating agent decitabine can increase Wnt target gene expression as measured in resected tumors compared to pretreatment biopsies in patients with primary colon cancer.
次要结局
- Tumor differentiation(30 minutes after surgery)
- Wnt target methylation.(30 minutes after surgery)
- Proliferation (Ki-67)(30 minutes after surgery)
- Apoptose (TNEL en M30 assay)(30 minutes after surgery)
- CIMP gene methylation(30 minutes after surgery)
- Beta-catenin localisation(30 minutes after surgery)
研究者
H.W.M. van Laarhoven
Dr.
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)