Dual systemic tumour targeting with ligand-directed phage and Grp78 promoter induces regression of glioblastoma
Dr. Amin Hajitou.
NB: This abstract won the “Best Scientific Abstract award at the 2012 British Neuro-oncology Society’s 2012 Annual Conference
The effects of current therapies against glioblastoma are limited and novel therapeutic approaches are required. Malignant brain tumours were one of the earliest targets for gene therapy and the failure of most clinical gene therapy seems to be mainly due to low tumour transduction. Integration of both ligand-directed tropism and transcriptional targeting into a single platform might facilitate clinical cancer gene therapy. The promoter of the glucose-regulated protein 78 (Grp78) and the ligand RGD that targets av-integrins specifically expressed in tumours, offer excellent candidates.
The stress-inducible Grp78 shows specific over-activation in aggressive tumours and encodes for an anti-apoptotic protein involved in tumour survival and drug resistance of glioblastoma. However, the clinical benefit of Grp78 promoter in gene therapy has been hindered by lack of efficacy via the systemic non-invasive route. We have generated a dual tumour targeted phage chimera containing the RGD ligand and Grp78 promoter.
The double-targeted phage provides persistent gene expression in glioblastoma cells invitro and in subcutaneous glioblastoma invivo after intravenous administration. Next, we found a systemic antitumor effect of Grp78-driven HSVtk therapeutic gene against recurrent glioblastoma invivo and uncovered a novel mechanism of Grp78 promoter activation by HSVtk and ganciclovir therapy. Finally, treatment of glioblastoma cells with temozolomide and cisplatin enhances HSVtk expression from Grp78 promoter.
Our data prove the potential of Grp78 promoter against glioblastoma and indicate that combination of chemotherapeutic drugs and the double-targeted phage should be considered in cancer patients.