Pre-operative Decitabine in Colon Cancer: a Proof of Principle Study
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.
Patients > 18 yr old with histopathologically proven or high suspicion of colon cancer.
Intervention: In patients with proven colon cancer, five extra biopsies will be taken from
the tumour during endoscopy to determine CpG methylation of Wnt target genes in fresh tumor
samples. Next, these patients will pre-operatively receive decitabine as a single
intravenous infusion at a dose of 45 mg/m2 over 6 hr. After resection, Wnt target gene
expression and CpG methylation of Wnt target genes will again be determined in fresh tumor
Main study parameters: The primary study parameter is Wnt target gene expression (APCDD1,
AXIN2, DKK1, LGR5 and ASCL2). Secondary study parameters are Wnt target and CIMP gene
methylation, beta-catenin localization, proliferation (Ki-67), apoptosis (TUNEL and M30
assay) and tumor differentiation.
Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label
Wnt target gene expression (APCDD1, AXIN2, DKK1, LGR5 and ASCL2)
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.
30 minutes after surgery
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)