David Hirst - Overview

Several factors contribute to the failure of current cancer treatments. These include the intrinsic phenotype of the tumour and molecular events that generate an unfavourable microenvironment. The evidence is now overwhelming that hypoxia in tumours is one of the most serious impediments to effective treatment. Hypoxic cells must, therefore, be considered as a prime target for intervention. The ability to target these cells without damaging normal tissues remains elusive, although bioreductive drugs seem likely to provide real therapeutic benefit. Gene therapy offers the prospect of improved targeting of hypoxic cells.

Work ongoing within our group aims to express nitric oxide synthase II (to generate high concentrations of nitric oxide, a hypoxia-specific radiosensitizer and pro-apoptotic free radical) and cytochrome P450s (to enhance the bioreduction of a variety of novel prodrugs, including AQ4N). When these strategies are used in combination with oxic cell killers, tumour cure should be a realistic goal. We also aim to target intrinsically radioresistant tumour cells by delivery of DIR1 (a recently discovered radiosensitizing gene). Targeting specificity for all transgenes will be achieved using a novel combination of radiation inducible promoters, to confine expression of the transgenes to the irradiated volume, and tissue specific promoters to confine expression to tumour cells. We have already demonstrated impressive anti-tumour responses using relatively simple methods.

The overall goal of our current research is to refine these gene therapy strategies in terms of delivery, targeted expression and scheduling to the point where their efficacy can be tested in the clinic.