Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02022995 |
| Other study ID # |
201310053RIND |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
December 22, 2013 |
| Last updated |
August 1, 2016 |
| Start date |
January 2014 |
| Est. completion date |
January 2016 |
Study information
| Verified date |
August 2016 |
| Source |
National Taiwan University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Taiwan: Department of Health |
| Study type |
Observational
|
Clinical Trial Summary
Protein arginine methylation is an important process, which regulates diverse cellular
functions including cell proliferation, RNA stability, DNA repair and gene transcription.
Based on literature search, protein arginine methyltransferase (PRMT) indeed plays important
roles in colon cancer pathophysiology. The PRMT expression level is involved in colon cancer
patient's survival and has been suggested to be a prognostic marker in colon cancer
patients. Recently, our group found a novel methylation on epidermal growth factor receptor
(EGFR), which affected EGFR downstream signaling. investigators further observed the
methylation event on EGFR not only regulated tumor growth in mouse xenograft model but also
influenced cetuximab response in colon cancer cell lines. To further study the clinical
correlation between EGFR methylation and cetuximab response, we propose to detect EGFR
methylation level in paraffin embedded tissue samples from colorectal cancer patients with
or without cetuximab treatment by IHC staining and analyze its correlation with cetuximab
response. This study will provide an insight to the strategy of colorectal cancer therapy.
Description:
Colorectal cancer is the third cause of cancer in the world. The recommended treatment of
early stage (stage I and stage II) colorectal cancer is surgical removal, while the
management of late stage (stage III and stage IV) colorectal cancer relies heavily on
chemotherapy. Optimization of dosing and scheduling of chemotherapy agents are developed to
improve response and survival rate of patients. Meanwhile, the rational targeting of
molecular signaling pathways that are involved in the etiology of malignancies is currently
one of the most promising strategies in novel anticancer drug development. Since first
discovery of EGFR in 1962, EGFR family and its downstream signaling has become one of the
most well characterized receptor tyrosine kinase system. In addition to their function in
normal development, aberrant expression of EGFR is involved in abnormal cell proliferation,
reduced apoptosis, cell migration, metastasis, angiogenesis and resistance to radiation and
chemotherapy in cancer patients. Owing to the important role that EGFR plays in
tumorigenesis, new classes of drugs that target EGFR, such as cetuximab, are among the most
clinically advanced molecular-targeted therapies. The combination of EGFR monoclonal
antibody with chemotherapy has shown efficacy in colorectal cancer treatment. However, the
resistance of EGFR target therapy was recently observed due to complicated and different
drug resistance mechanisms. Take EGFR monoclonal antibody, cetuximab, as an example, the
response rate of cetuximab-plus-irinotecan therapy was about 23%. Some studies showed the
resistance of EGFR to cetuximab is related to constitutive activation of mutant KRAS.
However, more and more studies showed not all wild type KRAS patients response to cetuximab,
while not all mutant Kras patients are refractory to cetuximab. These observations make it
urgent to investigate the potential EGFR regulation mechanisms that may influence and
predict the cetuximab response.
Epigenetic modifications, such as alterations in DNA methylation patterns and histone
changes, play critical roles in human disease. Since identification of protein arginine
methyltransferases (PRMTs), arginine methylation has been largely recognized and is under
robust investigation. During arginine methylation process, PRMTs transfer methyl groups from
S-adenosylmethionine (SAM) to guanidine nitrogenes of specific arginine residues on their
target proteins. After arginine methylation, protein structure, protein-protein interaction,
protein localization and enzyme activity are changed. As a result, diverse cellular
functions including signal transduction, RNA processing, DNA repair and gene transcription
are under regulation of arginine methylation. Recently, emerging evidences have shown links
between dysfunction of arginine methylation and cancers. In prostate cancer, H4R3
methylation by PRMT predicts the risk of cancer recurrence; in Mixed Lineage Leukaemia
(MLL), PRMT mediates transcriptional upregulation during cancer progression. Moreover,
aberrantly high expression of PRMT is observed in tumor tissues of both breast and
colorectal cancer and, notably, is associated with poor clinical outcomes in colorectal
cancer patients. Given the importance of PRMT and EGFR in colorectal cancer development and
progression, investigators tried to further investigate the relation between EGFR and PRMT
in colorectal cancer pathophysiology.
In our preliminary data, investigators found PRMT can methylate EGFR, leading to
up-regulation of EGFR signaling. The up-regulated EGFR signaling further triggered higher
cell proliferation rate. In addition, cells with higher EGFR methylation level showed higher
tumor growth ability in mice colorectal cancer xenograft model. Importantly, the cells with
higher EGFR methylation level demonstrated higher cell growth rate in the presence of
cetuximab in in vitro cell proliferation assay, suggesting that EGFR methylation may lead to
resistance to cetuximab. In order to study the clinical correlation between EGFR methylation
and cetuximab resistance, investigators propose to collect paraffin embedded tissue samples
from patients with or without cetuximab treatment and analyze their EGFR methylation level.
Investigators expect that patients with lower EGFR methylation level have higher improvement
when treated with cetuximab compared to those without cetuximab treatment. In contrast,
patients with higher EGFR methylation level showed poorer improvement when treated with
cetuximab in comparison with patients without cetuximab treatment. By detecting EGFR
methylation levels in these tissue samples and analyzing the correlation between EGFR
methylation level and cetuximab response, investigators will provide an insight for
prediction of cetuximab response in colorectal cancer therapy.
