Reports of research work funded by grants prior to 2013
Victoria University of Wellington
Developing Enzymes to Image and Target Tumours by Gene Therapy
JN Copp, DF Ackerley
School of Biological Sciences
Tumour-targeting viruses and bacteria hold great promise as anti-cancer agents. They kill cells by entirely different mechanisms to radio- and chemotherapies, and have potential to synergise with these treatments without overlapping toxicities. Furthermore, these agents can be ‘armed’ with genes that encode enzymes that activate prodrugs – compounds that are inert in their administered form, but become highly toxic upon activation. This not only improves killing of infected cells, but also neighbouring non-infected cells, as the activated prodrug can diffuse locally and exert a ‘bystander effect’. A critical limitation to date has been the inability to non-invasively monitor the location and amplification of viral and bacterial vectors in the body post-administration. To address this, we are using directed evolution (random genetic mutagenesis coupled with artificial selection for improved enzyme variants) to develop optimised Positron Emission Tomography (PET) imaging capable nitroreductases that also have enhanced prodrug activation and biosafety potential. These enzymes will ultimately facilitate uptake of enzyme-prodrug gene therapy into clinical trials, and accelerate development of self-replicating oncolytic biological agents.