An HSV-1 amplicon system for prostate-specific expression of ICP4 to complement oncolytic viral replication for in vitro and in vivo treatment of prostate cancer cells

Lee, Cleo; Bu, Luke; Rennie, Paul S.; Jia, William

doi:10.1038/sj.cgt.7701052

Cited by 22 publications

(30 citation statements)

References 42 publications

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“…All cell lines were maintained in DMEM supplemented with 10% fetal bovine serum and antibiotics containing penicillin and streptomycin. Vero and 7B cells are monkey kidney cells used to package amplicon viruses as described previously (16). LNCaP, DU145, and PC-3 are human prostate cancer cell lines and LNCaP-Luc is a derived stable cell line that expresses luciferase.…”

Section: Translational Relevancementioning

confidence: 99%

“…We have recently shown that a replication-defective HSV-1 helper virus (CgalΔ3), lacking the essential ICP4 gene, became oncolytic in a tissue type-specific fashion when the ICP4 gene was provided by an amplicon expressing this gene under the regulation of a prostate-specific promoter, ARR 2 PB (16). Although others have also attempted to incorporate tissue-specific promoters in front of suicide and/or essential viral genes to achieve specific killing of cancer cells, nonspecific toxicity to normal tissues due to leaky promoters has remained a problem (17,18) and suggests that improved stringency of oncolytic viral targeting needs to be developed.…”

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confidence: 99%

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MicroRNA Regulation of Oncolytic Herpes Simplex Virus-1 for Selective Killing of Prostate Cancer Cells

Lee

Rennie

Jia

2009

Clinical Cancer Research

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Purpose: Advanced castration-resistant prostate cancer, for which there are few treatment options, remains one of the leading causes of cancer death. MicroRNAs (miRNA) have provided a new opportunity for more stringent regulation of tumor-specific viral replication. The purpose of this study was to provide a proof-of-principle that miRNAregulated oncolytic herpes simplex virus-1 (HSV-1) virus can selectively target cancer cells with reduced toxicity to normal tissues. Experimental Design: We incorporated multiple copies of miRNA complementary target sequences (for miR-143 or miR-145) into the 3′-untranslated region (3′-UTR) of an HSV-1 essential viral gene, ICP4, to create CMV-ICP4-143T and CMV-ICP4-145T amplicon viruses and tested their targeting specificity and efficacy both in vitro and in vivo. Results: Although miR-143 and miR-145 are highly expressed in normal tissues, they are significantly down-regulated in prostate cancer cells. We further showed that miR-143 and miR-145 inhibited the expression of the ICP4 gene at the translational level by targeting the corresponding 3′-UTR in a dose-dependent manner. This enabled selective viral replication in prostate cancer cells. When mice bearing LNCaP human prostate tumors were treated with these miRNA-regulated oncolytic viruses, a >80% reduction in tumor volume was observed, with significantly attenuated virulence to normal tissues in comparison with control amplicon viruses not carrying these 3′-UTR sequences. Conclusion: Our study is the first to show that inclusion of specific miRNA target sequences into the 3′-UTR of an essential HSV-1 gene is a viable strategy for restricting viral replication and oncolysis to cancer cells while sparing normal tissues. (Clin Cancer Res 2009;15(16):5126-35)

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Section: Translational Relevancementioning

confidence: 99%

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confidence: 99%

MicroRNA Regulation of Oncolytic Herpes Simplex Virus-1 for Selective Killing of Prostate Cancer Cells

Lee

Rennie

Jia

2009

Clinical Cancer Research

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“…In this regard, HSV oncolytic vectors have been developed where different cancer-specific promoters were incorporated in front of an essential viral gene to achieve selective viral replication (in) and specific killing of cancer cells [139, 234, 249, 266]. However, nonspecific toxicity to normal tissue due to leaky promoters has remained a problems [358, 359] and suggests that improved stringency of oncolytic viral targeting needs to be developed. One approach to achieve this is to take advantage of unique tissue-associated patterns of expression of microRNAs (miRNA).…”

Section: New Perspectives In Tumour Oncolytic Virotherapymentioning

confidence: 99%

HSV Recombinant Vectors for Gene Therapy

Manservigi

Argnani²,

Marconi³

2010

TOVJ

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The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges.

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“…With our current technology this could most likely be attained using some sort of strategy employing a targeted, replication-competent oncolytic virus. 64,65 Alternatively, lentivirus coated with a targeting antibody could be used to express secretable proteins with anti-cancer properties and hence render a high-local concentration within the tumor.…”

Section: Her-2 Targeting Of Prostate Cancermentioning

confidence: 99%

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Moussavi

et al. 2009

Cancer Gene Ther

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In this study, we took advantage of the overexpression of human epidermal growth factor receptor 2 (HER-2) in prostate cancers to design lentiviruses with modified envelope proteins that bind antibodies to specific cell-surface antigens. When bound to trastuzumab (Herceptin, Genentech, CA), lentiviruses were able to selectively infect androgen-sensitive LNCaP and castrationresistant C4-2 human prostate cancer cell lines, both of which express high levels of HER-2. To test for a therapeutic effect, we engineered our antibody-binding lentiviruses to express thymidine kinase, which can convert the non-toxic pro-drug ganciclovir (GCV) into a cytotoxic form. LNCaP and C4-2 cells infected by these viruses were sensitive to GCV killing. In vivo, C4-2 xenograft tumors treated either intratumorally or i.v. with trastuzumab-bound lentivirus expressed luciferase, although the latter route was less tumor specific. When a prostate-specific promoter for governing luciferase expression was combined with trastuzumab-mediated delivery, there was a further enrichment in targeting viral gene expression in prostate tumors. In conclusion, we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody.

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An HSV-1 amplicon system for prostate-specific expression of ICP4 to complement oncolytic viral replication for in vitro and in vivo treatment of prostate cancer cells

Cited by 22 publications

References 42 publications

MicroRNA Regulation of Oncolytic Herpes Simplex Virus-1 for Selective Killing of Prostate Cancer Cells

MicroRNA Regulation of Oncolytic Herpes Simplex Virus-1 for Selective Killing of Prostate Cancer Cells

HSV Recombinant Vectors for Gene Therapy

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

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