Gerry Hammond, PhD

Cancers are caused by mutations that drive uncontrolled growth and proliferation of cells, and eventually unbridled migration. A common class of mutations is found in more than half of all cancer cases: those that activate a central lipid signaling pathway – the PI 3-kinase or PI3K pathway. The lipid products of this pathway activate downstream cellular programs promoting proliferation, survival and migration – all hallmarks of tumors.

So it seems like a good idea to stop this pathway with PI3K inhibitors, and big pharma has many compounds approved or in late-stage clinical development. The huge caveat is that PI3K is crucial for other processes in the body – such as activation of the immune system, and the cellular response to insulin. So, PI3K blockers are not well tolerated. We need a more nuanced approach.

We are studying the lipid products of PI3K. Whilst the pathway is famous, it is less well known that the pathway actually produces two signaling lipids – a major and minor lipid. We developed a biosensor for the latter (the rainbow colored image, above). We have also used gene editing to tag the enzymes involved so we can track their activity in intact cells. While no one really understood what this lipid is doing, we can now study it in real time.

The aim of the project is to test the hypothesis that this minor lipid actually drives long term proliferative signaling in tumors, whilst the major lipid is responsible for more acute effects of insulin or activation of the immune system. We therefore believe that down-regulating the minor lipid will selectively attenuate signaling in tumors, whilst sparing normal immunological and metabolic pathways elsewhere in the body. As an added bonus, this may actually improve insulin sensitivity and reduce the accumulation of tauopathy (as seen in Alzheimer’s disease). The project will involve training in live cell imaging, molecular genetics and gene editing in cell culture models.