Analyzing Role of PI3K Isoforms
Researchers at the Institute of Cancer at Barts and The London School of Medicine’s Center for Cell Signaling are investigating the role of PI3K isoforms in normal physiology and disease. “I thought there was something interesting about PI3k isoforms when I started in research 15 years ago,” said Bart Vanhaesebroeck, Ph.D., center lead. His group isolated the PI3K genes in various mammals and tried to use mouse knock-out models to understand gene function.
It turns out this strategy doesn’t work well for PI3K because it provides no good correlation to what inhibitors would do. Instead, Dr. Vanhaesebroeck decided to develop a model that would mimic what inhibitors do genetically.
The kinase knock-in mice have an active site with a mutation in an ATP-binding amino-acid residue, leading to inactivation of kinase. “The knock-in strategy is much more informative for drug development than the knock-out model—it’s a more real reflection of what a small molecule inhibitor will do.”
The first gene he cloned was the p110delta—one of the eight isoforms of PI3K. Expressed mainly in white blood cells, it is a good target for autoimmune diseases, allergies, inflammation, and leukemia. A p110delta PI3K knock-in mouse model was developed and worked well. Phenotypes seen in this model were more severe than in equivalent knock-out mice, “revealing some interesting biology in terms of immune signaling.” Additional research found the isoform important in controlling allergic reactions. “This biological work identified p110delta as one to go for in terms of drug development,” stated Dr. Vanhaesebroeck.
This research process was repeated with p110 alpha knock-in mice. This isoform has been found to be extremely important in insulin and metabolic signaling. Interestingly, when inactivated, the isoform does cause some changes in metabolic control, but does not induce diabetes. Further work has shown it also affects angiogenesis and blocks blood vessel formation.
The potential of PI3K as a drug target remains to be seen as clinical trials are still in the early stages. “I think you have to separate cancer from other diseases like inflammation, arthritis, etc. In noncancers, if you choose a PI3K isoform, you can overcome the complexity of the PI3K pathway because they are quite specialized in their function. But in cancer, the pathway, in my view, is universally unregulated. I think you have to hit all eight isoforms. It’s not going to be as toxic as everyone had thought, but dose-escalation studies are ongoing and we still need to see efficacy,” he concluded.