Optimizing targeted cancer therapy: Towards clinical application of systems biology approaches

In cancer, genetic and epigenetic alterations ultimately culminate in discordant activation of signal transduction pathways driving the malignant process. Pharmacological or biological inhibition of such pathways holds significant promise with respect to devising rational therapy for cancer. Thus, technical concepts pursuing robust characterization of kinase activity in tissue samples from cancer patients have been subject of investigation. In the present review we provide a comprehensive overview of these techniques and discuss their advantages and disadvantages for systems biology approaches to identify kinase targets in oncological disease. Recent advances in the development and application of array-based peptide-substrate kinase activity screens show great promise in overcoming the discrepancy between the evaluation of aberrant cell signaling in specific malignancies or even individual patients and the currently available ensemble of highly specific targeted treatment strategies. These developments have the potential to result in a more effective selection of kinase inhibitors and thus optimize mechanism-based patient-specific therapeutic strategies. Given the results from current research on the tumor kinome, generating network views on aberrant tumor cell signaling is critical to meet this challenge. (C) 2011 Elsevier Ireland Ltd. All rights reserved