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Abstract

The selection of appropriate targeted drugs relies on identification of molecular alterations in the tumor. Molecular pathology needs to be applied to identify them and characterize the molecular markers for predictive and prognostic purposes. In addition, the progression of cancer is driven by genetic alterations that lead to abnormal proteins and aberrations in signal transduction pathways. Signal transduction pathway proteins could serve as potential therapeutic targets. KRAS mutations is presently used as a predictor to anti-EGFR inhibitors, cetuximab and panitumumab therapy. Wild type BRAF has been discovered to be essential for response to these targeted therapies. BRAF with V600E mutation has been predicted to have poor survival in 5% of colorectal cancers (CRC). In our study, the frequency of Kras and BRAF mutations were 35% to ~45% and 2.3%, respectively which is lower than previous reports. One of the most commonly studied signaling pathways in CRC is the Wnt signaling pathway. The accumulation of cytoplasmic �²-catenin and translocation to the nucleus results in transcriptional activation of target genes that promote cell proliferation, survival and angiogenesis. Thus, blockade of this pathway has been of interest for cancer therapy. The Notch pathway is also an attractive pathway for targeted therapeutics. Notch signaling proteins such as Hes1, are highly expressed in tumor tissue compared to normal tissue. However, treatment of metastatic CRC patients with a Notch pathway inhibitor RO4929097 showed little to no effect. It is unclear whether the efficacy of Notch pathway inhibitors can be enhanced by combining inhibitors of other pathways such as Wnt signaling pathway. This study attempts to elucidate the relationship between Wnt and Notch signaling pathways in primary CRC tissues by DNA mutation analysis and immunohistochemistry. This project has provided information on the extent of the aberrations in these two signaling pathways and genetic alterations in Malaysian CRC cases and potentially can assist in the identification of new therapeutic targets.

Biography

Heng Fong Seow was graduated with BSc in Biomedical Sciences from the University of London, UK in 1982 and PhD from the University of Auckland, New Zealand in 1985. She was a Postdoctoral fellow at Stanford University, California and at IMCB, Singapore and Senior Scientist at CSIRO and Burnet Institute, Australia. She is currently a Professor of Molecular Immunology and her research interest is in the area of cancer molecular diagnostics and therapeutics and tumor immunology. She has published at least 120 papers and is on the Editorial Board of the Malaysian Journal of Pathology.

Email: shf@upm.edu.my