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Myxoma virus therapy for human embryonal rhabdomyosarcoma in a nude mouse model.

ABSTRACT: Rhabdomyosarcoma (RMS) is a devastating tumor of young people that is difficult to cure. To determine if oncolytic virus therapy can improve outcomes in individuals with RMS, myxoma virus expressing a red fluorescent protein (MYXV-red) was evaluated for antitumoral effects using a murine model of RMS. Fluorescent protein was expressed in four RMS cell lines inoculated with MYXV-red, indicating that these cells were semipermissive to MYXV infection. MYXV-red replication and cytopathic effects were further evaluated using human embryonal RMS (CCL-136) cells. Logarithmic growth of MYXV-red and significant cell death were observed 72 hours after inoculation with MYXV. The oncolytic effects of MYXV-red were then studied in nude mice that were injected subcutaneously with CCL-136 cells to establish RMS xenografts. Once tumors measured 5 mm in diameter, mice were treated with multiple intratumoral injections of MXYV-red or saline. The average final tumor volume and rate of tumor growth were significantly decreased, and median survival time was significantly increased in MYXV-red-treated mice (P-values =0.0416, 0.0037, and 0.0004, respectively). Histologic sections of MYXV-red-treated tumors showed increased inflammation compared to saline-treated tumors (P-value =0.0002). In conclusion, MXYV-red treatment of RMS tumors was successful in individual mice as it resulted in decreased tumor burden in eight of eleven mice with nearly complete tumor remission in five of eleven mice. These data hold promise that MYXV-red treatment may be beneficial for people suffering from RMS. To our knowledge, this is the first report of successful treatment of RMS tumors using an oncolytic poxvirus.

SUBMITTER: Kinn VG

PROVIDER: S-EPMC4996258 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Myxoma virus therapy for human embryonal rhabdomyosarcoma in a nude mouse model.

Kinn Veronica G VG Hilgenberg Valerie A VA MacNeill Amy L AL

Oncolytic virotherapy 20160808

Rhabdomyosarcoma (RMS) is a devastating tumor of young people that is difficult to cure. To determine if oncolytic virus therapy can improve outcomes in individuals with RMS, myxoma virus expressing a red fluorescent protein (MYXV-red) was evaluated for antitumoral effects using a murine model of RMS. Fluorescent protein was expressed in four RMS cell lines inoculated with MYXV-red, indicating that these cells were semipermissive to MYXV infection. MYXV-red replication and cytopathic effects wer ...[more]

PMID: 27579297

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Project description:BACKGROUND:Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). METHODS:We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. RESULTS:ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. CONCLUSION:Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

Dataset Information

Myxoma virus therapy for human embryonal rhabdomyosarcoma in a nude mouse model.

Publications

Myxoma virus therapy for human embryonal rhabdomyosarcoma in a nude mouse model.

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