Targeted Gene Delivery
Enhancement of Radiation Response with Targeted Gene Delivery
Researchers: KJ Harrington, C White, T Menghistu
Initial studies have focused on the use of virus-directed enzyme prodrug therapy (VDEPT) using replication-deficient adenoviral vectors containing the E. coli nitroreductase (NTR) gene with the CB1954 prodrug. This approach has been shown to enhance radiation-induced cell death in vitro and in vivo. Direct delivery of radiosensitising and/or immunomodulatory genes in the form of tumour necrosis factor alpha (TNF alpha) and/or GM-CSF by replication-competent herpes simplex virus-1 (HSV-1) vectors has been investigated in vitro, and in vivo studies are ongoing. Preliminary analyses of an attenuated Reovirus-3 vector in combination with radiation in vitro and in vivo are in progress. Viral vectors expressing the sodium iodide symporter (NIS) gene have been made as a means of exploiting the diagnostic and therapeutic role of radioactive iodine in cancers other than thyroid cancer. Constructs containing different tissue- and tumour-specific promoters have been designed. In vitro analyses have been performed in non-thyroid solid cancer (colorectal, head and neck) models. This programme of preclinical work is being carried out in the context of an active programme of clinical research for patients with head and neck cancer at the Royal Marsden and St George's Hospitals. A Phase I/II study of intratumoural administration of a replication-competent HSV-1 vector that expresses GM-CSF in patients with cutaneous relapse of cancer is nearing completion. A Phase I trial of systemically administered Reovirus-3 vectors at the Royal Marsden will be supported by laboratory assays of viral persistence, shedding and tumour colonisation. In addition, clinical trials of two agents that inhibit growth factor receptor signalling (EGFR, c-erbB2) in conjunction with chemotherapy and radiotherapy have begun to accrue.
External Funding: Cancer Research UK
In the Section of Cell and Molecular Biology (including the Cancer Research UK Centre for Cell and Molecular Biology)
