Augmented Therapeutic Efficacy of an Oncolytic Herpes Simplex Virus Type 1 Mutant Expressing ICP34.5 Under the Transcriptional Control of<i>musashi1</i>Promoter in the Treatment of Malignant Glioma

Kanai, Ryuichi; Tomita, Hideyuki; Hirose, Yuichi; Ohba, Shigeo; Goldman, Steven A.; Okano, Hideyuki; Kawase, Takeshi; Yazaki, Takahito

doi:10.1089/hum.2006.107

Cited by 26 publications

(17 citation statements)

References 33 publications

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“…(ii) Expression of inhibitors of PKR-mediated protein shutoff from other viruses, such as HCMV TRS1 or IRS1 (52), or the ␥34.5 homologous domain from cellular MyD116 (GADD34) (4). (iii) Targeted expression of ␥34.5 in cancer cells; transcriptionally through the use of tumor specific promoters, such as glioma selective nestin and musashi1 (23,24), or translationally through the use of a picornavirus IRES (10). Here, we have chosen to examine a deletion of the ␥34.5 BBD that was reported not to affect phosphatase activity (47).…”

Section: Discussionmentioning

confidence: 99%

Effect of γ34.5 Deletions on Oncolytic Herpes Simplex Virus Activity in Brain Tumors

Kanai

Zaupa

Sgubin

et al. 2012

J Virol

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101

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The ICP34.5 protein of herpes simplex virus (HSV) is involved in many aspects of viral pathogenesis; promoting neurovirulence, inhibiting interferon-induced shutoff of protein synthesis, interacting with PCNA and TBK1, inhibiting dendritic cell (DC) maturation, and binding to Beclin 1 to interfere with autophagy. Because of its key role in neuropathogenicity, the ␥34.5 gene is deleted in all oncolytic HSVs (oHSVs) currently in clinical trial for treating malignant gliomas. Unfortunately, deletion of ␥34.5 attenuates virus replication in cancer cells, especially human glioblastoma stem cells (GSCs). To develop new oHSVs for use in the brain and that replicate in GSCs, we explored the effect of deleting the ␥34.5 Beclin 1 binding domain (BBD). To ensure cancer selectivity and safety, we inactivated the ICP6 gene (UL39, large subunit of ribonucleotide reductase), constructing ICP6 mutants with different ␥34.5 genotypes: ⌬68HR-6, intact ␥34.5; ⌬68H-6, ␥34.5 BBD deleted; and 1716-6, ␥34.5 deleted. Multimutated ⌬68H-6 exhibited minimal neuropathogenicity in HSV-1-susceptible mice, as opposed to ⌬68H and ⌬68HR-6. It replicated well in human glioma cell lines and GSCs, effectively killing cells in vitro and prolonging survival of mice bearing orthotopic brain tumors. In contrast, 1716 and 1716-6 barely replicated in GSCs. Infection of glioma cells with ⌬68H-6 and 1716-6 induced autophagy and increased phosphorylation of eIF2␣, while inhibition of autophagy, by Beclin 1 short hairpin RNA (shRNA) knockdown or pharmacological inhibition, had no effect on virus replication or phosphorylated eIF2␣ (p-eIF2␣) levels. Thus, ⌬68H-6 represents a new oHSV vector that is safe and effective against a variety of brain tumor models.

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Section: Discussionmentioning

confidence: 99%

Effect of γ34.5 Deletions on Oncolytic Herpes Simplex Virus Activity in Brain Tumors

Kanai

Zaupa

Sgubin

et al. 2012

J Virol

Self Cite

101

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“…The G207 virus, with further deletion of its α47 gene and promoter gene of US11 gene, is deprived of its neovascularity inducing effect [2] (see above). Table 2 lists some ideas leading to the construction of new oncolytic herpesviruses [145,174,195,216]. Dying tumor cells engulfed by DCs form DC vaccines, inasmuch as mature DCs express tumor antigens not in a tolerogenic, but in an immunogenic manner.…”

Section: Herpesvirusesmentioning

confidence: 99%

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Sinkovics

Horváth

2008

Arch. Immunol. Ther. Exp.

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Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.

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“…A key issue in developing a safe and effective oncolytic virotherapy is the achievement of maximal killing of tumor cells while maintaining tumor specificity of viral targeting (13)(14)(15). 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).…”

mentioning

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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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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Augmented Therapeutic Efficacy of an Oncolytic Herpes Simplex Virus Type 1 Mutant Expressing ICP34.5 Under the Transcriptional Control ofmusashi1Promoter in the Treatment of Malignant Glioma

Cited by 26 publications

References 33 publications

Effect of γ34.5 Deletions on Oncolytic Herpes Simplex Virus Activity in Brain Tumors

Effect of γ34.5 Deletions on Oncolytic Herpes Simplex Virus Activity in Brain Tumors

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

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

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