M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma

Alexandra Pisklakova, Brienne McKenzie, Franz Zemp, Xueqing Lun, Rajappa S. Kenchappa, Arnold B. Etame, Masmudur Rahman, Karlyne Reilly, Shari Pilon-Thomas, Douglas McFadden, Ebba Kurz, Peter A. Forsyth

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background Myxoma virus (MYXV) is a promising oncolytic agent and is highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an antiapoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L-deficient MYXV construct would overcome BTIC resistance to MYXV. Methods We used patient-derived BTICs to evaluate the efficacy of M011L knockout virus (vMyx-M011L-KO) versus wild-type MYXV (vMyx-WT) and characterized the mechanism of virus-induced cell death in vitro. To extend our findings in a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L-KO efficacy with and without temozolomide (TMZ) in mBTIC0309-bearing mice. Results We demonstrated that vMyx-M011L-KO induces apoptosis in BTICs, dramatically increasing sensitivity to the virus. vMyx-WT failed to induce apoptosis as M011L protein prevented Bax activation and cytochrome c release. In vivo, intracranial implantation of mBTIC0309 generated tumors that closely recapitulated the pathological and molecular profile of human gliomas. Treatment of tumor-bearing mice with vMyx-M011L-KO significantly prolonged survival in immunocompetent - but not immunodeficient - mouse models, an effect that is significantly enhanced in combination with TMZ. Conclusions Our data suggest that vMyx-M011L-KO is an effective, well-tolerated, proapoptotic oncolytic virus and a strong candidate for clinical translation.

Original languageEnglish (US)
Pages (from-to)1088-1098
Number of pages11
JournalNeuro-Oncology
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Fingerprint

Myxoma virus
Oncolytic Viruses
Neoplastic Stem Cells
Glioblastoma
Brain Neoplasms
Cell Survival
Apoptosis
temozolomide
Glioma
Viruses
bcl-2-Associated X Protein
Cytochromes c
Neoplasms
Proteins
Cell Death
Animal Models
Recurrence
Survival

Keywords

  • Apoptosis
  • Brain tumor-initiating cells
  • Glioma
  • Oncolytic virus

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma. / Pisklakova, Alexandra; McKenzie, Brienne; Zemp, Franz; Lun, Xueqing; Kenchappa, Rajappa S.; Etame, Arnold B.; Rahman, Masmudur; Reilly, Karlyne; Pilon-Thomas, Shari; McFadden, Douglas; Kurz, Ebba; Forsyth, Peter A.

In: Neuro-Oncology, Vol. 18, No. 8, 01.08.2016, p. 1088-1098.

Research output: Contribution to journalArticle

Pisklakova, A, McKenzie, B, Zemp, F, Lun, X, Kenchappa, RS, Etame, AB, Rahman, M, Reilly, K, Pilon-Thomas, S, McFadden, D, Kurz, E & Forsyth, PA 2016, 'M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma', Neuro-Oncology, vol. 18, no. 8, pp. 1088-1098. https://doi.org/10.1093/neuonc/now006
Pisklakova, Alexandra ; McKenzie, Brienne ; Zemp, Franz ; Lun, Xueqing ; Kenchappa, Rajappa S. ; Etame, Arnold B. ; Rahman, Masmudur ; Reilly, Karlyne ; Pilon-Thomas, Shari ; McFadden, Douglas ; Kurz, Ebba ; Forsyth, Peter A. / M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma. In: Neuro-Oncology. 2016 ; Vol. 18, No. 8. pp. 1088-1098.
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abstract = "Background Myxoma virus (MYXV) is a promising oncolytic agent and is highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an antiapoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L-deficient MYXV construct would overcome BTIC resistance to MYXV. Methods We used patient-derived BTICs to evaluate the efficacy of M011L knockout virus (vMyx-M011L-KO) versus wild-type MYXV (vMyx-WT) and characterized the mechanism of virus-induced cell death in vitro. To extend our findings in a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L-KO efficacy with and without temozolomide (TMZ) in mBTIC0309-bearing mice. Results We demonstrated that vMyx-M011L-KO induces apoptosis in BTICs, dramatically increasing sensitivity to the virus. vMyx-WT failed to induce apoptosis as M011L protein prevented Bax activation and cytochrome c release. In vivo, intracranial implantation of mBTIC0309 generated tumors that closely recapitulated the pathological and molecular profile of human gliomas. Treatment of tumor-bearing mice with vMyx-M011L-KO significantly prolonged survival in immunocompetent - but not immunodeficient - mouse models, an effect that is significantly enhanced in combination with TMZ. Conclusions Our data suggest that vMyx-M011L-KO is an effective, well-tolerated, proapoptotic oncolytic virus and a strong candidate for clinical translation.",
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AU - McKenzie, Brienne

AU - Zemp, Franz

AU - Lun, Xueqing

AU - Kenchappa, Rajappa S.

AU - Etame, Arnold B.

AU - Rahman, Masmudur

AU - Reilly, Karlyne

AU - Pilon-Thomas, Shari

AU - McFadden, Douglas

AU - Kurz, Ebba

AU - Forsyth, Peter A.

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N2 - Background Myxoma virus (MYXV) is a promising oncolytic agent and is highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an antiapoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L-deficient MYXV construct would overcome BTIC resistance to MYXV. Methods We used patient-derived BTICs to evaluate the efficacy of M011L knockout virus (vMyx-M011L-KO) versus wild-type MYXV (vMyx-WT) and characterized the mechanism of virus-induced cell death in vitro. To extend our findings in a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L-KO efficacy with and without temozolomide (TMZ) in mBTIC0309-bearing mice. Results We demonstrated that vMyx-M011L-KO induces apoptosis in BTICs, dramatically increasing sensitivity to the virus. vMyx-WT failed to induce apoptosis as M011L protein prevented Bax activation and cytochrome c release. In vivo, intracranial implantation of mBTIC0309 generated tumors that closely recapitulated the pathological and molecular profile of human gliomas. Treatment of tumor-bearing mice with vMyx-M011L-KO significantly prolonged survival in immunocompetent - but not immunodeficient - mouse models, an effect that is significantly enhanced in combination with TMZ. Conclusions Our data suggest that vMyx-M011L-KO is an effective, well-tolerated, proapoptotic oncolytic virus and a strong candidate for clinical translation.

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