Abstract 4283: Myxoma virotherapy targeting temozolomide-resistant brain tumor initiating cells in vitro and in vivo
Authors: Lun Xueqing , Forsyth Peter A. , Senger Donna L. , Robbins Stephen , Kelly John J.p. , Weiss Samuel , Bell John , McFadden Grant 
Published: February 2011

Abstract
Introduction: Malignant gliomas (MGs) still has a poor prognosis and remain largely incurable because their extremely invasive nature, even with significant improvements in surgery, chemotherapy and radiotherapy. Although temozolomide (TMZ) improved the survival of some GBM patients, but recently TMZ resistant became a significantly problem. So new treatments could overcome the TMZ resistant desperately needed. Recently, cells with stem cell qualities have been identified in brain malignancies and have demonstrated brain tumor initiating cells (BTICs) responsible for the initiation of brain tumors and recurrence, as well as chemotherapy and radiotherapy resistant. Therefore, to development of new therapeutic strategies targeting BTICs may provide more effective approach. Oncolytic viruses may represent an effective therapeutic approach to target BTICs because their unique and multiple mechanism of action. We have previously reported that Myxoma Virus (MYXV) “cures” most intracranial brain tumors models in CD-1 nude mice, and significantly improved the efficacy in immunocompetent hosts when combined with rapamycin. Here we further investigated the oncolytic potential of MYXV, alone or in combination with rapamycin in vitro and in animal models established using human BTICs, special for TMZ resistant BTIC lines. Experimental procedure: First, we isolated and cultured BTICs from fresh operative glioblastoma (GBM) specimens, and these cells have all the characteristic of BTICs and form tumors in vivo that very closely resemble human infiltrative GBM. Then, we test the sensitivity to TMZ and we used TMZ resistant BTICs to test the susceptibility to MYXV infection in vitro and in vivo. Results: We found that: 1) All we tested TMZ resistant BTICs susceptible to MV infection and killing in vitro, 2) MYXV replication within TMZ resistant BTICs tumor of the brain and intratumoral administration of MYXV significantly prolongs survival of SCID mice bearing invasive BTICs tumor. 3) And more importantly we found that MYXV Combination treatment with rapamycin further improved the efficacy, even significantly prolongs survival of SCID mice bearing “late-stage” invasive and TMZ resistant BTICs tumor, and this result further confirmed using MRI and bioluminescence image before and after treatment. Conclusion: Our results show for the first time that MYXV alone or in combination treatment with rapamycin significantly inhibited tumor growth and prolongs survival in TMZ resistant BTICs bearing SCID mice models. These observations suggest that MYXV alone or in combination therapy with rapamycin could be an effective therapy for extremely infiltrative GBM, as well as the important TMZ adjuvant therapy for GBM in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4283.