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Molecular switch the key to breakthrough cures on many fronts

Publication date: Mar 21, 2006 4:23:52 PM

A single molecular switch may be the key to fighting disease on several fronts. Research published in Science this week, suggests that the blocking of one signalling pathway may be crucial in tackling auto-immune disease, transplant rejection and leukaemia.

Having identified a small family of signalling molecules that play an important role in cancer, researchers at the Ludwig Institute for Cancer Research at UCL have now found that one of its siblings dominates the initiation of immune response. The discovery, reported in the July 18 issue of Science, raises the possibility that targeting just one member of this group may block disorders that depend on this pathway - leukaemia and auto-immune diseases like arthritis in particular.

The study forms part of an ongoing effort to better understand how signalling systems inside cells are controlled by PI3-kinase, a group of enzymes that have generated considerable scientific interest because of their link to cancer. Under normal circumstances, PI3-kinase signalling affects the growth, movement and survival of cells. If not kept in check, though, the same signalling can cause cancer.

To simulate the effects of a drug that might block the actions of a specific PI3-kinase member, scientists genetically engineered mice in order that one of these molecules - called p110delta -was effectively switched off. The mice appeared healthy and there was no noticeable damage to the heart, liver, and most major organs. Under close inspection the mutated mice were unable to mount a normal immune response. Specifically, the mice revealed substantial defects in the activities of the B and T lymphocyte immune cells, two crucial components for defending the body against foreign invaders.

The findings suggest that inactivating p110delta - and thereby Band T lymphocyte cells, could help against arthritis and multiple sclerosis, auto-immune conditions where over active B and T cells not only fight infection, but start to attack healthy organs also leading to inflammation and tissue damage.

Speaking on the publication of the research, Dr Bart Vanhaesebroeck of the Ludwig Institute for Cancer Research at UCL, said: "By targeting the p110delta signalling pathway alone, you could potentially design a medicine that hits the immune system quite hard but with fewer side effects than current drugs like steroids."

Drugs that block the p110delta signalling pathway may also be useful in organ transplants where the rejection mechanism originates from lymphocyte cells in either the donor or the transplant patient. A similar treatment strategy may also keep B and T cells from dividing out of control and causing leukaemia. The ground breaking cancer drug, Gleevec, has produced dramatic results by blocking a kinase signal in much the same way.

Dr Vanhaesebroeck concluded: "Our results raise the exciting possibility that targeting the p110delta pathway may be used in the treatment of Leukaemia's, although we are still a long way from testing this idea in a clinical setting."