Aykut Uren1, Jeffrey A Toretsky. 1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Abstract
PURPOSE OF REVIEW: Improving overall survival and reducing morbidity are major goals of childhood cancer research. This review explores an old idea that increased survival in childhood cancer can be achieved by inhibiting specific cancer targets. Specific therapeutic targeting would theoretically cause reduced morbidity as well as increased survival. Tumor-specific translocation-generated fusion proteins appear to be ideal tumor-specific therapeutic targets. This review will describe advances in aspects of target identification, potential for small molecule screening, and the evolution of clinical resistance to this new generation of pharmaceuticals. RECENT FINDINGS: Advances in molecular biology have identified new protein targets along with increased understanding of the biologic role of these proteins. Ewing sarcoma family of tumors research has benefited from new target discovery and enhanced biologic understanding of the EWS-FLI1 fusion protein. Congenital (infantile) fibrosarcoma and cellular mesoblastic nephroma have been grouped based on the presence of a common translocation fusion protein, ETV6-NTRK3. Functional knowledge of ETV6-NTRK3 has advanced so that strategies for screening small molecule inhibitors can proceed. Patients with chronic myeloid leukemia have benefited from the discovery of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec), thus showing how a molecular therapeutic target can be inactivated for improved therapy. This review will describe challenges raised by clinical resistance to imatinib mesylate as a paradigm for how resistance might evolve in other disease models. This review also describes how patients with synovial sarcoma might benefit from future therapy directed towards the SYT-SSX family of fusion proteins. SUMMARY: The increased utilization of small molecules to disrupt or inactivate tumor-specific molecular targets is rapidly evolving. The use of these small molecules to probe biology and treat disease is advancing towards a new generation of anticancer therapies.
PURPOSE OF REVIEW: Improving overall survival and reducing morbidity are major goals of childhood cancer research. This review explores an old idea that increased survival in childhood cancer can be achieved by inhibiting specific cancer targets. Specific therapeutic targeting would theoretically cause reduced morbidity as well as increased survival. Tumor-specific translocation-generated fusion proteins appear to be ideal tumor-specific therapeutic targets. This review will describe advances in aspects of target identification, potential for small molecule screening, and the evolution of clinical resistance to this new generation of pharmaceuticals. RECENT FINDINGS: Advances in molecular biology have identified new protein targets along with increased understanding of the biologic role of these proteins. Ewing sarcoma family of tumors research has benefited from new target discovery and enhanced biologic understanding of the EWS-FLI1 fusion protein. Congenital (infantile) fibrosarcoma and cellular mesoblastic nephroma have been grouped based on the presence of a common translocation fusion protein, ETV6-NTRK3. Functional knowledge of ETV6-NTRK3 has advanced so that strategies for screening small molecule inhibitors can proceed. Patients with chronic myeloid leukemia have benefited from the discovery of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec), thus showing how a molecular therapeutic target can be inactivated for improved therapy. This review will describe challenges raised by clinical resistance to imatinib mesylate as a paradigm for how resistance might evolve in other disease models. This review also describes how patients with synovial sarcoma might benefit from future therapy directed towards the SYT-SSX family of fusion proteins. SUMMARY: The increased utilization of small molecules to disrupt or inactivate tumor-specific molecular targets is rapidly evolving. The use of these small molecules to probe biology and treat disease is advancing towards a new generation of anticancer therapies.
Authors: Shilpi Arora; Irma M Gonzales; R Tanner Hagelstrom; Christian Beaudry; Ashish Choudhary; Chao Sima; Raoul Tibes; Spyro Mousses; David O Azorsa Journal: Mol Cancer Date: 2010-08-18 Impact factor: 27.401