Sensitization of (colon) cancer cells to death receptor related therapies

Abstract

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.

Keywords: :

• cancer
• death receptors
• kinase inhibitors
• mitochondria
• oncogenes
• rational combinations
• targeted therapies

Conflict of Interest

P. Workman and P.A. Clarke are employees of The Institute of Cancer Research, which has a commercial interest in the development of PI3K and HSP90 inhibitors and operates a rewards-to-inventors scheme. P. Workman and his team have been involved in a commercial collaboration with Yamanouchi (now Astellas Pharma) and with Piramed Pharma, and intellectual property on PI3K inhibitors arising from the program has been licensed to Genentech. P. Workman was a founder of, consultant to, Scientific Advisory Board member of, and stockholder in Piramed Pharma, which was acquired by Roche. P. Workman and his team have also been involved in a commercial collaboration with Vernalis and intellectual property on HSP90 inhibitors arising from the program has been licensed to Novartis. P. Workman has been a consultant to Novartis. Juan Carlos Lacal is a government employee of CSIC, an Agency of the Spanish Department of Economy and Competitiveness, that has a commercial interest in the development of choline kinase inhibitors as therapeutic drugs. JC Lacal is a founder and stockholder of TCD Pharma, a company which has been licensed for the commercial exploitation of choline kinase inhibitors from CSIC.

Acknowledgments

This work is supported by the EU grant LSHC-CT-2006–037278 “ONCODEATH.”