The development of viral vectors for use in Gene-directed enzyme prodrug therapy (GDEPT)
Supervisor(s): Professor Caroline Springer
Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)
Team: Gene and Oncogene Targeting Team
View full details of this PhD Studentship in PDF format
Summary
GDEPT (Gene-Directed Enzyme Prodrug Therapy) using the bacterial enzyme carboxypeptidase G2 (CPG2) is a two-step treatment for cancer. In the first step, we aim to use a viral vector to target the foreign CPG2 gene selectively to the tumour. The development of the vector is crucial as it directs the expression of the CPG2 in the tumour. In the second step, after expression of CPG2 at the tumour, a prodrug is administered. The prodrug is a non-toxic drug precursor that is activated by the CPG2 to a cytotoxic drug.
We plan to construct vaccina viral vectors with CPG2 and luciferase genes so that these two enzymes will be expressed in a range of human tumour cells and xenografts. The vectors will be assessed in vitro and in vivo for efficacy in targeting the CPG2 gene to tumours as well as examination of the biodistribution of CPG2 in normal tissues and blood. The reporter luciferase enzyme will be imaged with an IVIS machine (a 3D optical in vivo imaging system), which shows the location of luciferase in the human tumour cells and xenografts
The ultimate goal is to develop an alternative vector to our clinically approved adenoviral vector, AdV.hTERT-CPG2, a vector that targets the CPG2 gene directly to the tumour but that does not contain luciferase for IVIS imaging. It is anticipated that the new vaccinia vector will have the advantages that we can assess real-time luciferase targeting in vivo and thus optimise the scheduling of the prodrug in the second step of the treatment.
References
Schepelmann, S., et al (2008). Attenuated Salmonella targets prodrug activating enzyme CPG2 to mouse melanoma, human breast and colon carcinomas for effective suicide gene therapy. Clin Cancer Res Vol 14, No 13, p4259-4266
Schepelmann, S., et al (2007). Suicide gene therapy of human colon carcinoma xenografts using an armed oncolytic adenovirus expressing carboxypeptidase G2. Cancer Res Vol 67, No 10, p4949-4955
Hedley, D, et al (2007). Carboxypeptidase G2-based gene-directed enzyme prodrug therapy: a new weapon in the GDEPT armoury. Nature Rev Cancer Vol 7, No 11, p870-879
Schepelmann, S., et al (2005). Systemic gene-directed enzyme prodrug therapy of different hepatocellular carcinoma xenografts using a targeted adenovirus armed with carboxypeptidase G2. Cancer Res Vol 65, No 12, p5003-5008
Niculescu-Duvaz, D., et al (2003). Self-immolative nitrogen mustard prodrugs cleavable by carboxypeptidase G2 (CPG2) showing large cytotoxicity differentials in GDEPT. J Med Chem Vol 46 No 9, p1690-1705
Friedlos, F., et al(2002). Three new prodrugs for suicide gene therapy using CPG2 elicit bystander efficacy in two xenograft models. Cancer Res Vol 62, No 6, p1724-1729
Springer, C.J., et al (2000). Prodrug-activating systems in suicide gene therapy. J Clin Invest Vol 105, No 9, p1161-1167
Marais, R.M., et al (1997). Extra cellular expression of the carboxypeptidase G2 enzyme for activation of a mustard prodrug in Gene-directed enzyme prodrug therapy. Nature Biotech Vol 15, p1373-1377
Marais, R.M., et al (1996). Gene-directed enzyme prodrug therapy with a mustard prodrug/carboxypeptidase G2 combination. Cancer Res Vol 56, No 20, p4735-4742
