Grant: Project Grant

One of the major developments in cancer treatment has been the use of cancer immunotherapy to utilise the immune system to target and destroy cancer cells. The phosphoinositide 3-kinase (PI3K) pathway is at the crossroads of both cancer development and immune regulation, with mutations in this pathway being extremely frequent in the development and maintenance of multiple high mortality human cancers. Intriguingly, inhibition of the PI3K gamma isoform is able to act as a switch that can reprogram the tumour microenvironment to target cancer cells. This is a powerful approach to promote the immune system to generate an anti-cancer response. In addition, the PI3K gamma isoform is also frequently upregulated in many cancers, with the development of specific inhibitors being an excellent strategy for cancer therapeutics. This proposal focuses on studying the structural and dynamic basis of regulation of PI3K gamma, with a major focus on the development of specific small molecule inhibitors. One of our major goals will be in defining the molecular mechanisms that control how this enzyme is activated, and how it can be misregulated in human disease. This will be approached using a cutting-edge synergy of state of the art biochemical and biophysical methods including Cryo-Electron Microscopy, X-ray crystallography, and Hydrogen Deuterium Exchange mass spectrometry. A powerful team of collaborators including medicinal chemists, cell biologists, and clinical immunologists has been established to fully apply biophysical discoveries in both cellular and organism models of disease. PI3K gamma is an exceptionally important target for anti-cancer therapeutics. This proposal focusing on defining the molecular basis of how this enzyme is regulated will reveal novel insight into its role in immune regulation and cancer immunotherapy. The development of small molecule inhibitors in this proposal has the potential to act as therapeutics in cancer therapy.