Oncolytic Herpes Simplex Virus Vector G47Δ in Combination with Androgen Ablation for the Treatment of Human Prostate Adenocarcinoma

Fukuhara, Hiroshi; Martuza, Robert L.; Rabkin, Samuel D.; Ito, Yoshikazu; Todo, Tomoki

doi:10.1158/1078-0432.ccr-05-1090

Cited by 61 publications

(55 citation statements)

References 16 publications

(20 reference statements)

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“…In contrast, G47D replication was not significantly abrogated in AdPMLpre-infected cells at any MOI. In agreement with earlier reports, 38,39 these data suggest that VSVD51-GFP efficiently kills tumor cells that possess defects in IFN or PML signaling, whereas G47D replicates efficiently in tumor cells regardless of IFN or PML status.…”

Section: Pml and Ifn-sensitive Oncolytic Virusessupporting

confidence: 93%

PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

et al. 2009

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The oncotropic phenotypes of several viruses correlate with tumor-associated deficiencies within interferon (IFN) signaling pathways. This observation formed the conceptual basis for developing oncolytic viruses deleted for viral proteins that inhibit the host IFN-dependent antiviral response, such as herpes simplex virus type-1 infected cell protein-0 (ICP0) and vesicular stomatitis virus matrix protein. Many viruses have evolved means to disrupt promyelocytic leukemia protein (PML) nuclear bodies. For example, ICP0 promotes PML degradation to inhibit the antiviral activities of this IFN-stimulated gene. As PML is downregulated in a variety of tumors, we hypothesized ICP0-null herpes simplex type-1 viruses are selectively oncolytic in tumors with impaired PML expression. We illustrate that ICP0-null herpes simplex type-1 viruses target tumor cells that either possess impaired PML signaling or cannot upregulate PML because of impaired IFN responsiveness. Disruption of PML signaling through overexpression of the dominant-negative protein PML-retinoic acid receptor alpha in PML-positive cells renders them sensitive to oncolysis by ICP0-null herpes simplex virus type-1 and vesicular stomatitis virus M protein mutant viruses, whereas PML overexpression reverses this phenomenon. Together, these data illustrate that PML mediates an antiviral mechanism that predicts the tropism of IFN-sensitive oncolytic viruses. To our knowledge, these viruses are the first examples of anti-cancer therapeutics capable of targeting deficiencies in PML expression.

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Section: Pml and Ifn-sensitive Oncolytic Virusessupporting

confidence: 93%

PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

et al. 2009

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“…(b) Oncolytic HSV mutants, including G207 and NV1020, have shown efficacy against human prostate cancer xenografts and mouse prostate cancers following intraneoplastic or i.v. administration (14)(15)(16)(17). (c) G207 and other vectors are effective against human prostate cancer irrespective of hormone status or radiosensitivity (14,16,18)-a major advantage in its application for advanced forms of the disease in which hormone-and radiation-refractory tumor is an inevitable progression.…”

Section: Introductionmentioning

confidence: 99%

Systemic Therapy of Spontaneous Prostate Cancer in Transgenic Mice with Oncolytic Herpes Simplex Viruses

et al. 2007

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Oncolytic viruses are an innovative therapeutic strategy for cancer, wherein viral replication and cytotoxicity are selective for tumor cells. Here we show the efficacy of systemically administered oncolytic viruses for the treatment of spontaneously arising tumors, specifically the use of oncolytic herpes simplex viruses (HSV) administered i.v. to treat spontaneously developing primary and metastatic prostate cancer in the transgenic TRAMP mouse, which recapitulates human prostate cancer progression. Four administrations of systemically delivered NV1023 virus, an HSV-1/HSV-2 oncolytic recombinant, to TRAMP mice at 12 or 18 weeks of age (presence of prostate adenocarcinoma or metastatic disease, respectively) inhibited primary tumor growth and metastases to lymph nodes. Expression of interleukin 12 (IL-12) from NV1042 virus, a derivative of NV1023, was additionally effective, significantly reducing the frequency of development of prostate cancer and lung metastases, even when the mice were treated after the onset of metastasis at 18 weeks of age. NV1042-infected cells, as detected by 5-bromo-4-chloro-3-indolyl-B-D-galactopyranoside staining for Lac Z expressed by the virus, were present in prostate tumors 1 week after the final virus injection and viral DNA was detected at 2 weeks after final virus injection by real-time PCR in primary and metastatic tumors but not in liver or blood. No toxicity was observed in any of the treated mice. The efficacy of the IL-12-expressing NV1042 virus in this aggressive prostate cancer model using a clinically relevant treatment paradigm merits its consideration for clinical studies.

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“…Both G207 and [ [51][52][53][54][55][56] G47delta target the human cancer specimens specifically. However, G47delta has better efficacy of replication than that of G207 and exhibits greater cytopathic effects in xenogenic models and majority of cell lines [29,30].…”

Section: An Overview Of Hsvmentioning

confidence: 99%

Advance in herpes simplex viruses for cancer therapy

Liu

Dai

You

et al. 2013

Sci. China Life Sci.

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Oncolytic virotherapy is an attractive approach that uses live viruses to selectively kill cancer cells. Oncolytic viruses can be genetically engineered to induce cell lyses through virus replication and cytotoxic protein expression. Herpes simplex virus (HSV) has become one of the most widely clinically used oncolytic agent. Various types of HSV have been studied in basic or clinical research. Combining oncolytic virotherapy with chemotherapy or radiotherapy generally produces synergic action with unclear molecular mechanisms. Arming HSV with therapeutic transgenes is a promising strategy and can be used to complement conventional therapies. As an efficient gene delivery system, HSV has been successfully used to deliver various immunomodulatory molecules. Arming HSV with therapeutic genes merits further investigation for potential clinical application.

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Oncolytic Herpes Simplex Virus Vector G47Δ in Combination with Androgen Ablation for the Treatment of Human Prostate Adenocarcinoma

Cited by 61 publications

References 16 publications

PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

PML has a predictive role in tumor cell permissiveness to interferon-sensitive oncolytic viruses

Systemic Therapy of Spontaneous Prostate Cancer in Transgenic Mice with Oncolytic Herpes Simplex Viruses

Advance in herpes simplex viruses for cancer therapy

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