UBC Theses and Dissertations
Enhancement of oncolytic herpes simplex type 1 virotherapy Delwar, Zahid M.
Despite excellent safety data, antitumor efficacy of the oncolytic herpes simplex virus type 1 (oHSV-1) in glioblastoma (GBM) patients is not satisfactory. A major enhancement of the oncolytic activity of the oHSV-1 is necessary to eradicate the GBM in clinics. To enhance the efficacy and tumour specificity, we first developed a GBM specific triple regulated oHSV-1 amplicon system (SU4-124 HSV-1). Translational regulation was achieved by incorporating five copies of microRNA 124 target sequences into the 3’UTR of the ICP4 gene. Additionally, a 5'UTR of rat fibroblast growth factor -2 was added in front of the viral ICP4 gene open reading frame. The SU4-124 HSV-1 demonstrated enhanced tumour specificity and stronger anti-tumour efficacy compared to the tumour non specific CMV- ICP4 HSV-1 in both in-vitro and in-vivo GBM models. We then examined the effect of a potent STAT inhibitor, which is the key regulator of interferon (IFN) response, nifuroxazide (NF), a prescription anti-diarrheal drug, on the oHSV-1 efficacy. This was done with the aim of reinforcing the anti-tumour efficacy of oHSV-1 and developing an effective combination therapy. Here, we found that NF synergistically augments the anti-tumour efficacy of oHSV-1 by regulating the anti-apoptotic properties of HSV-1 in various tumour cells. Moreover, our data demonstrated that STAT1/3 activation mediated the underlying cellular mechanism of this novel combination. To further improve the efficacy of oHSV-1, possible barriers in the microenvironment of GBM need to be identified. Since previous clinical GBM have documented an abundance of microglia /macrophages, we first investigated the interaction of oHSV-1 and microglia/macrophages in in-vitro and in-vivo GBM models. We found evidence that microglia/macrophages suppress oHSV-1 in glioma mass by generating a physical barrier to the dissemination of oHSV-1. We also observed that the deficiencies in viral replication in microglial cells are associated with the STAT1/3-mediated silence of particular viral genes. We found that an oxindole/imidazole derivative, C16, can aid the viral replication in microglia/macrophages and dramatically increase the therapeutic efficacy of oHSV-1 in GBM animal model. In conclusion, this project outlines possible ways to overcome the barriers involved in oHSV-1 therapy to successfully eradicate clinical GBM.
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