Cell Signalling Processes and Developmental Neurobiology

Biography

As an Associate Professor at UCL in London, I have pursued a career from my PhD in 1986 until today, in the areas of cancer cell biology and developmental neurobiology. I have a particular interest in cell signaling processes and their roles in developing neuronal cells and in neuronal cancer cells. Much of my career has focussed on tyrosine kinase and phosphatase actions in cancer and also in the control of nerve formation and repair, and neurogenesis. This has culminated in my present research interest in a pediatric, neural cancer, neuroblastoma. My team has studied tyrosine phosphatase enzymes as suppressors and drivers in this cancer, and we have developed new approaches for delivering chemical inhibitors to tumour cells in order to enhance neuronal differentiation. I have also developed a strong interest in enhancing the anti-cancer actions of the biologic retinoic acid in this disease and we are currently developing new toxin delivery systems that are sensitive to this drug. My primary goal is to provide new avenues for therapeutics development in this childhood cancer.

Research

My research group has historically focussed on understanding the roles of phosphotyrosine signalling in the area of oncogenesis and in the developmental context of axonogenesis and neurogenesis. Since 1988 I developed a particular interest in understanding the roles of the tyrosine-specific phosphatases (PTPs) and was the first to demonstrate the location of a receptor PTP (RPTP) in embryonic, vertebrate axons and 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 RPTP ligands demonstrated the first proteoglycan ligand for PTPsigma, heparan sulphate. This finding went on to influence several international teams to discover that these RPTPs play important roles in synapse formation and nerve repair.

In 2008 I turned my attention again to molecular oncology, with my interest focussing on nervous system cancers, particularly neuroblastoma. This was of relevance to our interests in PTPs, given that neuroblastoma is a developmental cancer, and some current treatments use the tumour cell’s capacity to differentiate back into neurons. We initially focussed on oxidovanadium compounds (PTP inhibitors) as potential therapeutics. We showed for the first time that such PTP inhibitors enhance neuronal differentiation and senescence in tumour-derived cell lines, and also enhance the actions of retinoic acid, a biological used in neuroblastoma residual disease treatment. We have shown that there are hydrophobic oxidovanadium derivatives that can be delivered to tumour cells using liposomes, and that these also enhance retinoic actions. Focussing further on retinoic acid, we demonstrated that retinoid catabolism can be blocked with CYP26 inhibitors, again delivered using liposomes, thereby enhancing retinoic acid’s ability to drive differentiation and to limit tumour cell proliferation. These studied served as a proof of principle that retinoic acid actions and metabolism can be targeted in tumour cells using novel implementations of hydrophobic inhibitors and nanotechnology. These areas are of interest in the longer term for their potential to enhance residual disease treatment in patients.

More recently we have focussed on further, distinct approaches for enhancing retinoic acid-based therapy in neuroblastoma. We are currently developing retinoid-sensitive, toxin delivery systems for these tumour cells, again using nanoparticle delivery approaches, and hope to provide avenues for development of new and effective therapeutics.

Lastly, from our previous research on PTP inhibition, we identified potential new drivers of neuroblastoma tumour cell behaviour. One of these is the protein HMMR (also known as RHAMM), as complex protein with hyaluronic acid binding properties, but also nuclear actions. We have recently shown that this protein sustains proliferation and motility in neuroblastoma cells and may support tumour growth in vivo (unpublished). We are pursuing research to understand HMMR’s molecular signaling roles in neuroblastoma and thereby develop a clear picture of this protein’s effectors as potential therapeutic sensitivities.

We have PhD projects on offer in the Child Health Research portfolio. Prospective students are invited to apply before 12/01/2024. Applicants are required to select projects of interest from the portfolio and contact supervisors before applying. See: https://www.ucl.ac.uk/child-health/study/postgraduate-research-programmes/child-health-research-phd-project-portfolio-202425