Therapeutics targeting signal transduction for patients with colorectal carcinoma.
The cytotoxics developed for the treatment of patients with advanced colorectal cancer have yielded diminishing returns. Agents aimed at novel molecular targets are required to improve the prognosis of this disease. This review describes the most recent advances in the clinical development of therapies designed to block the function of several important signalling cellular proteins. Therapies discussed include agents targeting: (i) the epidermal growth factor receptor (EGFR) family; (ii) Ras via the inhibition of farnesyltransferase; (iii) Raf kinase; (iv) the mitogen-activated protein kinase pathway (MAPK, MEK, Erk); (v) Akt; and (vi) the apoptosis signalling pathways including NF-kappaB, Bcl-2 and the TRAIL receptor. The results of clinical trials of the first generation of such therapeutics to enter clinical evaluation in malignant diseases are presented. Potential advantages and disadvantages of these different therapeutic modalities are discussed and future challenges for the evaluation of these targeted agents in the clinic is presented.
de Bono
Johann S
JS
Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach Road, 4th Floor Zeller Building, San Antonio, TX 78229, USA.
Rowinsky
Eric K
EK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000628:therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D066246:ErbB Receptors / Q000276:immunology; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D000068818:Cetuximab