My research group has historically focussed on understanding the roles of phosphotyrosine signalling, first in oncogenesis and later in axonogenesis and neurogenesis. Since 1988 I have had particular interest in understanding the roles of the tyrosine-specific phosphatases (PTPs). I was the first to demonstrate the location of a receptor PTP (RPTP) in embryonic axons and that this RPTP localised to growth cones. We went on to show a role in neurite formation in culture and a novel role in controlling retinotectal axon targeting in avian embryos. We also demonstrated roles of another RTP, PTPgamma, in spinal motor neuron development in the chick embryo. Our subsequent research with Radu Aricescu into RPTP ligands demonstrated the first proteoglycan ligand for PTPsigma, heparan sulphate. This finding went on to help several international teams to discover that these RPTPs play important, novel roles in synapse formation and nerve repair.

In 2008 I turned my attention again to molecular oncology, applying my knowledge to nervous system cancers. We initially focussed on oxidovanadium compounds (PTP inhibitors) as potential therapeutic platforms in neuroblastoma. We showed that such PTP inhibitors enhance the actions of retinoic acid, a biological used in neuroblastoma residual disease treatment. The inhibitors induce increased neuronal differentiation and senescence in tumour-derived cell lines and we also discovered that oxidovanadium synergises with inhibitors of glutathione synthesis to drive cytotoxicity in neuroblastoma cells. Both of these areas are of interest in the longer term for potentially enhancing residual disease treatment in patients.

Our subsequent objectives have included the identification of PTP family members that have “oncogene-like” behaviours in neuroblastoma cells. Our loss-of-function screens with shRNA, siRNA and most recently CRISPR/Cas9, have identified a number of candidate PTPs that we are now investigating. By defining their biochemical function, and effector pathways, we hope to be able to pinpoint suitable targets for future therapeutic intervention.

Recently we have expanded our interests in new approaches for enhancing retinoic acid-based therapy. Working with collaborators in Cardiff we have demonstrated that inhibitors of retinoid catabolism that block CYP26 function can double the ability of retinoic to induce differentiation and to limit tumour cell proliferation. However, these inhibitors are highly hydrophobic, and are very difficult to administer to humans. We have thus also provided the first proof of principle that such inhibitors can be delivered to tumour cells using liposome-based nanotechnology. This may lead to the future application of such inhibitors in pre-clinical testing.