Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer worldwide. Approximately
25% of newly diagnosed patients have already developed metastases,and 50%of all colorectal cancer patients will develop metastases over time as the disease progresses. Systemic therapy was restricted to fluoropyrimidine (5-FU)-based regimens alone or in combination with oxaliplatin or irinotecan for many years
Survival of patients with metastatic colorectal cancer (mCRC) has been significantly improved with the introduction of the monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). Novel molecular-targeted agents such as aflibercept and regorafenib have recently been approved.
VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer.
Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF. On June 20, 2006, the FDA granted approval for a labeling extension for bevacizumab, administered in combination with intravenous 5-fluorouracil based chemotherapy, for the second-line treatment of metastatic carcinoma of the colon or rectum. This recommendation is based on the demonstration of a statistically significant improvement in overall survival (OS) in patients receiving bevacizumab plus FOLFOX4 (5-flourouracil, leucovorin, and oxaliplatin) when compared to those receiving FOLFOX4 alone.
Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin. As a VEGF inhibitor, it is approved for the treatment of colorectal cancer.
Regorafenib is an oral multi-kinase inhibitor developed which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer and has been approved by the US FDA on September 27, 2012.
Epidermal growth factor receptor (EGFR) belongs to a family of receptors known as the ErbB family (ErbB tyrosine kinase receptors) which comprises four proteins encoded by the c-erbB proto-oncogene. EGFR is known to activate a cascade of multiple signaling pathways that facilitate tumor growth process. EGFR has been shown to be overexpressed in colorectal cancer patient populations. The development of a panel of EGFR inhibitors could reduce the proliferation of tumor cells when used alone or in combination with cytotoxic drugs or radiation.
Cetuximab, a chimeric IgG1 monoclonal antibody that binds to the extracellular domain of EGFR, blocks ligand-induced receptor signaling and modulates tumor-cell growth. Cetuximab has activity in colorectal cancer and can reverse drug resistance in patients with colorectal cancer when administered with irinotecan.
Panitumumab is a 100% human IgG2 anti-EGFR mAb developed using XenoMouse technology.Panitumumab was approved for monotherapy of relapsed/refractory mCRC by the US Food and Drug Administration in September 2006 and conditionally approved (in patients with tumours harbouring wild-type KRAS) by the European Medicines Agency (EMEA) in December 2007.
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