One Molecular Switch May be Key to Fighting Several Diseases

Having identified a small family of signaling molecules that play an important role in cancer, researchers at the Ludwig Institute for Cancer Research now find that one of these siblings dominates the conversation when initiating an immune response. The discovery, reported in the journal Science and posted July 18th on the Science Express Web site, raises the possibility that targeting just one member of this group may block disorders that depend on this pathway, such as leukemia and autoimmune diseases like arthritis.

The study is part of an ongoing effort to better understand how signaling systems inside cells are controlled by PI3-kinase (phosphoinositide 3-kinase), a group of enzymes that have generated intense research interest because of their link to cancer. Under normal circumstances, PI3-kinases make signals that affect the growth, movement, and survival of cells. But when these enzymes are not kept in check, the same signals can cause cancer.

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

These findings suggest that inactivating p110delta--and thus B and T cells--could help against arthritis and multiple sclerosis, autoimmune conditions where overactive B and T cells not only fight infections but start to attack healthy organs, leading to inflammation and tissue damage.

"By targeting just the p110delta signaling pathway, you could potentially design a medicine that hits the immune system quite hard but with fewer side effects than current drugs like steroids," said the study's lead author, Dr. Bart Vanhaesebroeck, of the Ludwig Institute for Cancer Research, University College London Branch.

Drugs that block p110delta might also be useful in organ transplants, which can be rejected by lymphocyte cells in the donor or transplant patient. A similar treatment strategy might also keep B and T cells from dividing out of control and causing leukemia. The groundbreaking cancer drug, Gleevec, has produced dramatic results by blocking another kinase signal in much the same way.

"Our results raise the exciting possibility that targeting the p110delta pathway may be used in the treatment of leukemias, although we are still a long way from testing this idea in the clinic" said Dr. Vanhaesebroeck.