Ludwig Institute for Cancer Research

London (July 18th)—Having discovered a 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 on the Science Express website, 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 eight 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.

Investigators at the Ludwig Institute have been working on PI3-kinases for the past 15 years and were the first to clone many of its members. Since discovering the PI3-kinase member p110delta, Dr. Bart Vanhaesebroeck of the Ludwig’s University College London Branch has been intrigued by the fact that this enzyme is only expressed in white blood cells. In the current study, he teamed up with Dr. Klaus Okkenhaug, an immunologist at the Ludwig Institute, and the Center for Genome Research in Edinburgh, to find out what role p110delta plays in the body’s defense system.

They decided to design mice in which p110delta is still present but is no longer effective, providing a realistic picture of what would happen if a drug blocked just this one enzyme. The mice appeared perfectly healthy and there was no noticeable damage to the heart, liver, and other major organs. Under closer inspection, however, the mutated mice were no longer able to mount a normal immune response. Specifically, the animals showed substantial defects in the activities of the B and T lymphocyte cells, two crucial components for initiating an immune response.

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 Dr. Vanhaesebroeck.

Drugs that block p110delta might also be useful to stop rejection of organ transplants, a process in which lymphocyte cells in the donor or transplant patient play a major role.

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. ‘This study is an important first step in finding out what these key signalling enzymes do’

By Eric Sabo and Dr. Khatereh Ahmadi

Abstract

Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002 Aug 9;297(5583):1031-4. [PMID: 12130661]