Investigation of Methylation of EGFR in the Response of the Cetuximab in Metastatic Colorectal Cancer Patients
Condition: Colon Cancer Adenocarcinoma
MeSH terms: Colonic Neoplasms
Study type: Observational

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.
    

Detailed 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.
    

Observational model: Case-Control
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Age between 20-80 years old Patient had surgery in NTUH
      
Keywords: EGFR; cetuximab; colon cancer