title: M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor-initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our data suggest that vMyx-M011L-KO is an effective, well-tolerated, proapoptotic oncolytic virus and a strong candidate for clinical translation.
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pisklakova
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Brienne
authors.initials: B
authors.lastname: McKenzie
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Franz
authors.initials: F
authors.lastname: Zemp
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Rajappa S
authors.initials: RS
authors.lastname: Kenchappa
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Etame
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Masmudur M
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Karlyne
authors.initials: K
authors.lastname: Reilly
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Shari
authors.initials: S
authors.lastname: Pilon-Thomas
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Ebba
authors.initials: E
authors.lastname: Kurz
authors.affiliation: Department of Neuro-Oncology and Tumor Biology, Moffitt Cancer Center, Tampa, Florida (A.P., R.S.K., A.B.E., P.A.F.); Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada (B.M., F.Z., X.L., E.K., P.A.F.); Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida (M.M.R., G.M.); Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (K.R.); Department of Immunology, Moffitt Cancer Center, Tampa, Florida (S.P.-T.).
authors.forename: Peter A
authors.initials: PA
authors.lastname: Forsyth
keywords: apoptosis; brain tumor-initiating cells; glioma; oncolytic virus