Development of a WNT-selective oncolytic adenovirus for imaging the therapy of colorectal cancers.

Abstract

Introduction: The concept of oncolytic adenoviruses has been validated in preclinical studies but clinical trials have demonstrated that the virus spread remains limited and the virus fails to infect all cancer cells in a tumour. Arming an oncolytic virus with a therapeutic trans gene would enhance the antitumour effect of these viruses by killing adjacent non-infected cells. The aim of this thesis is to test armed oncolytic adenoviruses targeting a constitutive activation of the Wnt signalling pathway in pre-clinical models of colorectal cancer. Methods: The Nail symporter was inserted into the genome of Wnt-selective oncolytic adenoviruses to visualise adenoviral spread in the tumour and assess image-guided radiotherapy. Results: In vitro testing of the virus has demonstrated that the Wnt-selectivity of the virus remains intact. The virus we generated has an equal or greater cytopathic effect than wild type adenovirus in Wnt-expressing cancer cell lines. The ability of the infected cells to take up iodine has been confirmed by iodine uptake assays. The virus has been injected into subcutaneous human tumour implants in nude mice. Images obtained with a SPECT/CT camera have demonstrated that viral propagation can be visualised in vivo. Finally, we have used the imaging data to determine the correct timing for the administration of therapeutic doses of 131 I. Conclusion: We have validated a non invasive method to image viral propagation and transgene expression in a preclinical model of colonic cancer. Sequential imaging can provide information on the ideal time point for therapeutic intervention. In pilot experiments, the aim was to exploit the potential of the Nail symporter for the concentration of radioactive iodine, but it did not lead to increased therapeutic efficacy in vivo in preclinical models. There is strong evidence that if these experiments were repeated, therapeutic efficacy could he demonstrated.