PI3 Kinase Pathway in Tumour Angiogenesis and Metastasis
Tumour Biology and Metastasis Team
Section: Cancer Research UK Cancer Therapeutics Unit
The phosphatidylinositol 3 (PI3) kinase pathway is frequently misregulated in cancer. We are using quantitative assays of invasion and angiogenesis in order to study the functional role of its components in tumour progression. Inhibitors of class 1A isoforms of PI3 kinase inhibit tumour cell motility and invasion in vitro and in vivo. Endothelial cell proliferation, migration, chemotaxis, haptotaxis and tubule differentiation in vitro are also blocked by these agents, and tumour microvessel density in vivo is reduced. Selective inhibitors and siRNA show that different isoforms may play distinct roles.
We have shown that novel inhibitors developed in collaboration with Yamanouchi Pharmaceuticals and PIramed (Slough, UK) are potent inhibitors of the growth and metastasis of human tumour xenografts where loss of the PTEN gene or other genetic abnormalities (such as PIK3CA mutations) leads to upregulated PI3 kinase pathway activity. The therapeutic effects correlate with inhibition of pharmacodynamic markers such as phosphorylation of AKT and GSK3β, assayed by western blot and MesoScale Discovery ELISA. We are also investigating the potential of these inhibitors for efficacy in models where induction of resistance to other agents is associated with an upregulated PI3K pathway.
Similar studies are underway with AKT/PKB inhibitors developed in collaboration with Astex (Cambridge, UK).
In the Cancer Research UK Cancer Therapeutics Unit
