Gillian Tozer - Overview

The Tumour Microcirculation Group investigates the abnormal structure and function of the tumour vasculature at the molecular/cellular and solid tumour levels. Translational work is carried out with clinicians at Mount Vernon Hospital.

Severe hypoxia is prevalent in tumours and is an adverse prognostic indicator. Our studies contributed to the ARCON trials (addition of carbogen-breathing and nicotinamide administration to accelerated fractionated radiotherapy). Investigations of the effects of nicotinamide and hyperoxic breathing gases on microregional tumour blood flow led to a Phase III clinical trial, combining 2% CO2/98% O2 with nicotinamide, for radiotherapy of bladder cancer (BCON trial, Dr Peter Hoskin, Cancer Research UK Clinical Tumour Biology and Radiation Therapy Group). We are investigating gene therapy strategies for exploiting tumour hypoxia. A new gene directed enzyme prodrug therapy (GDEPT) approach, based on the plant enzyme horseradish peroxidase is currently being tested (see Dr Gabi Dachs, this web site).

NO-producing pathways are up-regulated in tumours, hypoxia being one stimulus for the inducible form of nitric oxide synthase (iNOS). Systemic, non-isoform specific, inhibition of NOS produced a sustained decrease in tumour blood flow in experimental systems, with very little effect in normal tissues. Specific inhibition of iNOS had no effect on tumour blood flow. High levels of NO induce transcription of the inducible form of haemoxygenase (HO-1), which catalyses the oxidation of haem to the biologically active molecules iron (a gene regulator), biliverdin (an antioxidant) and carbon monoxide (a haem ligand and vasodilator). We have found high levels of HO-1 in solid tumours and are investigating its role in tumour blood flow control, angiogenesis and vascular-targeted therapy.

We have identified tubulin-destabilizing drugs as vascular-damaging in tumours, via disruption of the endothelial cell cytoskeleton. Extensive pre-clinical work led to the lead compound, combretastatin A-4-P (CA-4-P), entering clinical trials. We showed that CA-4-P caused a rapid and extensive shut-down of blood flow in experimental tumours, leading to tumour necrosis. Cancer Research UK-funded clinical results, using magnetic resonance imaging techniques (with Professor Gordon Rustin, Clinical Oncology Department, Mount Vernon Hospital), were consistent with a significant reduction in tumour blood flow in a majority of patients treated with high dose CA-4-P. We are developing and validating clinical methods for monitoring treatment-induced vascular damage.

We are studying the mechanism of action of tubulin-binding, vascular-targeted drugs. We have identified the importance of cell signalling pathways, in particular activation of the GTPase Rho and its associated Rho kinase (see Dr Chryso Kanthou, this web site). Neutrophil recruitment to the damaged endothelium plays an important part in the cytotoxic effect of CA-4-P and post-translational modifications of tubulin involving NO may influence the amount of vascular damage inflicted (see Dr Charles Parkins, this web site). In collaboration with Dr Boris Vojnovic within our institute, we are using 2-photon fluorescence techniques and intravital microscopy for identifying the characteristics of the tumour vasculature, which dictate susceptibility to drugs such as CA-4-P. Translational studies are designed to identify the most appropriate ways of combining vascular-targeted drugs with conventional treatments and new vascular-targeted drugs are being tested.