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PCRF-funded project underpins new drug development research

11 March 2013

Professor Tony Magee and Dr Ed Tate from Imperial College London have secured a development grant from Cancer Research UK to take their research to the crucial next stage, thanks to a project funded by Pancreatic Cancer Research Fund which started in 2011.

 Professor Magee, Dr Tate and their team are interested in a group of proteins called ‘Hedgehogs’ which usually play a role in instructing cells in embryos to grow into different body parts. However, the sequence of signals (or ‘signalling pathway’) activated by Hedgehog proteins is also active in 70% of pancreatic tumours, wrongly promoting cell growth.

 For the pathway to be active in tumours, an enzyme called ‘Hhat’ has to coat the proteins in fats, allowing them to stick to healthy cells. This causes the healthy cells to release molecules that ultimately promote tumour growth. The Magee/Tate PCRF project is working to identify the mechanisms behind this and investigate how the Hhat enzyme can be prevented from coating Hedgehog proteins in fats.

 It is this important PCRF-funded work that has underpinned Professor Magee and Dr. Tate winning a £200,000 CRUK grant to step up their search for compounds that prevent this process from happening.

 The 2-year CRUK ‘Discovery’ grant, which will start in April 2013, funds the development of a high-throughput screening test for Hhat antagonists - compounds that inhibit or dampen the effect of Hhat. Once this is done, the team will screen a library of 300,000 sample compounds housed at the Institute of Cancer Research in Sutton, Surrey, looking for those which show a potentially useful effect on Hhat.

 High-throughput screening is a highly specialised technology made possible through advances in robotics and high-speed computing. It allows researchers to conduct thousands of tests very rapidly to identify active compounds which have a desired effect on a target biomolecular pathway. The results of these experiments provide a starting point for drug discovery.

 Says Professor Magee: “We applied to CRUK last year for this grant but were turned down, with feedback advising that further work was needed before a project of this type would be considered for funding. Under our PCRF project we were able to undertake a number of further experiments to make this crucial ‘next-stage’ application fundable. We applied again and were successful, so the PCRF funding was absolutely pivotal to winning the CRUK grant. Since funding is increasingly harder to come by, this is fantastic news.”

 “With such a large library of compounds, we’re confident that we’ll get a decent number of initial ‘hits’, and we’ll need to investigate and validate these further, whittling them down to a handful of lead compounds that have the strongest potential. Drug discovery can be a numbers game and the vast majority of initially interesting compounds will be discarded along the way, but to have the funding to screen for possible target compounds is the crucial next step in this long journey. For us, this has only been possible by the Pancreatic Cancer Research Fund seeing the potential in our early ideas and backing our original work,” he said.

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