الفهرس 
Pathogenesis and targets of colorectal cancerOnly 14 pages are availabe for public view
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Abstract
Colorectal cancer is the third most common type of cancer and the third leading cause of cancer mortality in worldwide. About 72% of new CRC cases arise in the colon and the remaining 28% arise in the rectum. In Egypt, Colorectal cancer contributes 6.5% of all of total number of cancer cases reported annually. (Atlanta et al., 2011)
Management of colorectal cancer (CRC) has been impacted by the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. Recently, CRC has been reclassified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. At the same time, a number of new prognostic and predictive biomarkers have been discovered to reflect sensitivity and/or resistance to existing therapies. Other markers have been successfully used to predict toxic effects of standard therapies. (Jeffry et al., 2010)
For decades, 5-fluorouracil (5-FU) ± leucovorin (LV) was the only active agent in the treatment of advanced colorectal cancer with an overall response rate of 10% and a median survival of up to 12 months. At the end of the 1990s, the topoisomerase-1 inhibitor irinotecan and the platinum derivative oxaliplatin were introduced as active drugs in the treatment of metastatic CRC.Clinical trials concluded that capecitabine and oxaliplatin are both effective first-line treatment of metastatic CRC options with similar survival and efficacy. (Montagnani et al.,2011)
Over the last two decades, a better understanding of the processes involved in the transformation of normal cells into cancer cells has led to the development of new drugs called targeted therapies. The term targeted therapy refers to drugs that selectively target specific molecular pathways involved in tumor progression. Although traditional cytotoxic chemotherapies demonstrate some degree of selectivity by targeting cancer cells that are dividing, they are usually not considered targeted therapy since they are less selective and affect pathways that are common to normal tissues and tumors. In fact, the distinction between more conventional chemotherapy agents and targeted therapies is somewhat artificial since both may affect normal signaling pathways that can result in systemic toxicites. (Ogino et al., 2009)
Three targeted agents had been approved by the US Food and Drug Administration for management of advanced CRC: bevacizumab, cetuximab, and panitumumab. The monoclonal antibodies against the EGFR (cetuximab and panitumumab) had been developed and approved; another approach to inhibit cancer growth is the use of anti-angiogenic agents such as bevacizumab, which is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF). (Van cutsem et al., 2007)
Several randomized trials in patients with metastatic CRC included that anti-EGFR antibody therapy have specifically evaluated the impact of the mutational status of KRAS (wild-type versus mutated) on patient outcome. Notably, the presence of a KRAS mutation was found to be associated with the absence of biological and clinical activity for the anti-EGFR antibody treatment. (Folprecht et al., 2010)
Approximately 30% to 50% of colorectal tumors are known to have a mutated (abnormal) KRAS, indicating that up to 50% of patients with CRC might respond to anti-EGFR antibody therapy. Unfortunately, at least 40% to 60% of KRAS wild type patients will derive no benefit from anti EGFR antibodies, highlighting the need for additional targeted agents to by pass the KRAS pathway and inhibit other receptor tyrosine kinase signaling. (Adams et al., 2011)
Additional novel classes of agents are under development in clinical trials for treatment of patients with colorectal cancer such as targeting the VEGF and EGFR pathway via the associated tyrosine kinas, SRC inhibitors, PARP inhibitors, endothelin receptor antagonist, S100A4 inhibitors, immunomodulatory drugs, proteasome inhibitors, antisense drugs, therapeutic cancer vaccines and gene therapy. (American society of clinical oncology, 2011)