On the 'trail' for new solid tumour therapies A European research programme has made significant headway in the treatment of solid tumours. The scientists used structure-based design to develop molecules that are most likely to initiate cell death pathways where they are required. Health © Thinkstock In Europe alone, there are three million new cases of cancer each year and, with an ageing population, the situation is set to get a lot worse. Recent research has pinpointed the potential of tumour-selective agents to improve the treatment of solid tumours. Activating the chemical cascades that lead to cell death is an avenue of research that has huge potential in cancer therapy. The EU-funded 'Therapeutic molecules for treatment of solid tumours by modulating death receptor-mediated apoptosis' (Trident) project aimed to develop new therapeutic strategies using this principle. The technology behind the Trident project centred on the tumour necrosis factor ligand (TNF-L) family of molecules. When bound to their receptors TNF-Ls initiate programmed cell death, or apoptosis. The TNF-L family is very varied and includes TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FASL), both of which induce cell death. Trident designed the research to pick out which TNF-L members would make realistic therapeutic targets and under what biochemical conditions. Project scientists also aimed to generate TRAIL variants with advanced death-inducing characteristics by rational structure computer-assisted design. Previous studies had demonstrated that TRAIL only induced apoptosis via the DR4 or the DR5 receptor. Mutants produced by site-directed mutagenesis and replacement of two amino acids in the wild type TRAIL gave the required results, significantly increasing selectivity towards DR4. Another TRAIL variant targeting the DR5 receptor showed superior pro-apoptotic properties and produced less non-functional receptor complexes. The Trident project developed production protocols for purifying TRAIL variants that were candidates for pre- and early clinical studies. Pre-clinical animal studies were started and were ongoing at the close of the project. Future plans include exploitation of the Trident knowledge base for commercial application.
