Sensitization of (colon) cancer cells to death receptor related therapies A report from the FP6-ONCODEATH research consortium

• Published in: Cancer biology & therapy Vol. 13; no. 7; pp. 458 - 466
• Main Authors: Pintzas, Alexander, Zhivotovsky, Boris, Workman, Paul, Clarke, Paul A., Linardopoulos, Spiros, Martinou, Jean-Claude, Lacal, Juan Carlos, Robine, Sylvie, Nasioulas, George, Andera, Ladislav
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.05.2012
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Cycle; death receptors; Enzyme Inhibitors - administration & dosage; Humans; kinase inhibitors; Landes; Medicin och hälsovetenskap; mitochondria; Molecular Targeted Therapy; oncogenes; Organogenesis; Proteins; rational combinations; Receptors, Death Domain - antagonists & inhibitors; Receptors, Death Domain - metabolism; Signal Transduction - drug effects; targeted therapies
• ISSN: 1538-4047; 1555-8576; 1555-8576
• DOI: 10.4161/cbt.19600

The objective of the ONCODEATH consortium [EU Research Consortium "ONCODEATH" (2006-2010)] was to achieve sensitization of solid tumor cells to death receptor related therapies using rational mechanism-based drug combinations of targeted therapies. In this collaborative effort, during a period of 42 mo, cell and animal model systems of defined oncogenes were generated. Exploitation of generated knowledge and tools enabled the consortium to achieve the following research objectives: (1) elucidation of tumor components which confer sensitivity or resistance to TRAIL-induced cell death; (2) providing detailed knowledge on how small molecule Hsp90, Aurora, Choline kinase, BRAF inhibitors, DNA damaging agents, HDAC and DNMT inhibitors affect the intrinsic apoptotic amplification and execution machineries; (3) optimization of combined action of TRAIL with these therapeutics for optimum effects with minimum concentrations and toxicity in vivo. These findings provide mechanistic basis for a pharmacogenomic approach, which could be exploited further therapeutically, in order to reach novel personalized therapies for cancer patients.