Development of a WNT-selective oncolytic adenovirus for imaging the therapy of colorectal cancers.
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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.
Authors
Peerlinck, Inge D. L.Collections
- Theses [3831]