Tumour gene erects 'road blocks' against gene therapy traffic
CANCER RESEARCH UK scientists have discovered that an overactive cancer gene can block the delivery of gene therapy to its target - the nucleus. Reducing this gene's activity could improve the effectiveness of anti-cancer gene therapy according to research published in The Journal of Clinical Investigation* today (Friday).
A research team** based at Barts and The London School of Medicine and Dentistry part of Queen Mary, University of London, 'blocked' the activity*** of a gene called CEACAM6**** which is often hyperactive in a range of human tumours including breast, pancreas, liver, prostate, bowel and non-small-cell lung cancers.
They found for the first time that CEACAM6 overactivity can prevent a specially constructed gene transporter - called an adenovirus vector - being able to 'infect' cancer cells with corrective gene therapy molecules.
Their experiments showed that, rather than preventing the virus from entering the cell - to deliver the gene therapy - CEACAM6 blocked the transport of virus particles.
In effect, the hyperactive gene erects a 'road block', preventing the virus' path to the nucleus.
They also found that blocking CEACAM6 increased the survival of cancer-carrying mice treated with an anti-cancer adenovirus.
Their research suggests that cell signalling pathways activated by overactive CEACAM6 could become targets for the development of better gene therapy. They believe that tests could be developed to predict patient response to genetic therapy delivered by adenovirus vehicles.
Study author, Dr Yaohe Wang, a Cancer Research UK scientist at Queen Mary University, said: "We discovered that this gene puts a call out to set up 'road blocks' which prevent the gene therapy vehicle reaching its destination - the nucleus.
"Now we know how the gene blocks the journey of gene therapy molecules we can look for ways to lift the blockade or find ways around it."
Gene therapy is a very promising approach for treating cancer. New therapies such as adenoviral-p53 therapy are already being used to treat head and neck cancer. The performance of these new therapies on their own has been disappointing in trials so far, but it is evident that combination with other drugs improves their effectiveness. This new work opens the possibility of using a new class of drugs to boost the anti-cancer power of gene therapy.
Dr Lesley Walker, Cancer Research UK's director of cancer information said: "These exciting results are a big step forward in developing more effective gene therapy and to better predict patients’ response."
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Notes to Editor
* CEACAM6 attenuates adenovirus infection by antagonizing viral trafficking in cancer cells. Yaohe Wang et al. The Journal of Clinical Investigation. Volume119. Number 6. June 2009.
**The research team was led by led by Professor Nick Lemoine.
***They used a small molecule called interference RNA - an artificial strand of RNA which binds to a cell’s DNA - and stops it working.
****carcinoembryonic antigen-related cell adhesion molecule