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Author Jahan, N.; Lee, J.M.; Shah, K.; Wakimoto, H. url  doi
openurl 
  Title Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus Type Journal Article
  Year 2017 Publication International Journal of Cancer Abbreviated Journal Int J Cancer  
  Volume 141 Issue 8 Pages 1671-1681  
  Keywords Animals; Apoptosis/physiology; Brain Neoplasms/drug therapy/*therapy/virology; Cell Line, Tumor; Cohort Studies; Dacarbazine/analogs & derivatives/pharmacology; Drug Resistance, Neoplasm; Glioblastoma/drug therapy/*therapy/virology; HEK293 Cells; Humans; Mice; Neoplasm Recurrence, Local/drug therapy/therapy/virology; Neoplastic Stem Cells/drug effects/pathology/*virology; Oncolytic Virotherapy/*methods; Simplexvirus/genetics/*physiology; TNF-Related Apoptosis-Inducing Ligand/biosynthesis/genetics; TNF-related apoptosis inducing ligand (TRAIL); glioblastoma; oncolytic herpes simplex virus; recurrence; temozolomide  
  Abstract Temozolomide (TMZ) chemotherapy, in combination with maximal safe resection and radiotherapy, is the current standard of care for patients with glioblastoma (GBM). Despite this multimodal approach, GBM inevitably relapses primarily due to resistance to chemo-radiotherapy, and effective treatment is not available for recurrent disease. In this study we identified TMZ resistant patient-derived primary and previously treated recurrent GBM stem cells (GSC), and investigated the therapeutic activity of a pro-apoptotic variant of oHSV (oHSV-TRAIL) in vitro and in vivo. We show that oHSV-TRAIL modulates cell survival and MAP Kinase proliferation signaling pathways as well as DNA damage response pathways in both primary and recurrent TMZ-resistant GSC. Utilizing real time in vivo imaging and correlative immunohistochemistry, we show that oHSV-TRAIL potently inhibits tumor growth and extends survival of mice bearing TMZ-insensitive recurrent intracerebral GSC tumors via robust and selective induction of apoptosis-mediated death in tumor cells, resulting in cures in 40% of the treated mice. In comparison, the anti-tumor effects in a primary chemoresistant GSC GBM model exhibiting a highly invasive phenotype were significant but less prominent. This work thus demonstrates the ability of oHSV-TRAIL to overcome the therapeutic resistance and recurrence of GBM, and provides a basis for its testing in a GBM clinical trial.  
  Address Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language (up) English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0020-7136 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28567859 Approved no  
  Call Number ref @ user @ Serial 96584  
Permanent link to this record
 

 
Author Yan, H.; Romero-Lopez, M.; Benitez, L.I.; Di, K.; Frieboes, H.B.; Hughes, C.C.W.; Bota, D.A.; Lowengrub, J.S. url  doi
openurl 
  Title 3D Mathematical Modeling of Glioblastoma Suggests That Transdifferentiated Vascular Endothelial Cells Mediate Resistance to Current Standard-of-Care Therapy Type Journal Article
  Year 2017 Publication Cancer Research Abbreviated Journal Cancer Res  
  Volume 77 Issue 15 Pages 4171-4184  
  Keywords Brain Neoplasms/*pathology; Cell Transdifferentiation/physiology; Endothelial Cells/*pathology; Glioblastoma/*pathology; Humans; *Models, Theoretical; Neoplastic Stem Cells/*pathology  
  Abstract Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, cross-talk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Furthermore, GSC also transdifferentiate into bona fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional antiangiogenic therapies. Here we use three-dimensional mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSCs drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with antiangiogenic therapies reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSCs and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GECs maintain GSCs. Our study suggests that a combinatorial regimen targeting the vasculature, GSCs, and GECs, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication. Cancer Res; 77(15); 4171-84. (c)2017 AACR.  
  Address Center for Complex Biological Systems, University of California, Irvine, California  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language (up) English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0008-5472 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28536277 Approved no  
  Call Number ref @ user @ Serial 96585  
Permanent link to this record
 

 
Author Thomas, A.A.; Abrey, L.E.; Terziev, R.; Raizer, J.; Martinez, N.L.; Forsyth, P.; Paleologos, N.; Matasar, M.; Sauter, C.S.; Moskowitz, C.; Nimer, S.D.; DeAngelis, L.M.; Kaley, T.; Grimm, S.; Louis, D.N.; Cairncross, J.G.; Panageas, K.S.; Briggs, S.; Faivre, G.; Mohile, N.A.; Mehta, J.; Jonsson, P.; Chakravarty, D.; Gao, J.; Schultz, N.; Brennan, C.W.; Huse, J.T.; Omuro, A. url  doi
openurl 
  Title Multicenter phase II study of temozolomide and myeloablative chemotherapy with autologous stem cell transplant for newly diagnosed anaplastic oligodendroglioma Type Journal Article
  Year 2017 Publication Neuro-Oncology Abbreviated Journal Neuro Oncol  
  Volume 19 Issue 10 Pages 1380-1390  
  Keywords 1p/19q codeletion; anaplastic oligodendroglioma; autologous stem cell transplant; temozolomide  
  Abstract Background: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy. Methods: Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 x 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day x 3 days, then busulfan 3.2 mg/kg/day x 3 days), followed by ASCT. Genomic characterization was performed using next-generation sequencing. Results: Forty-one patients were enrolled; 85% had 1p/19q codeleted tumors. After induction, 26 patients were eligible for HDC-ASCT and 21 agreed to proceed. There were no unexpected adverse events or toxic deaths. After median follow-up of 66 months, 2-year progression-free survival (PFS) for transplanted patients was 86%, 5-year PFS 60%, and no patient has died. Among all 1p/19q codeleted patients (N = 33), 5-year PFS was 50% and 5-year overall survival (OS) 93%, with median time to radiotherapy not reached. Next-generation sequencing disclosed typical oligodendroglioma-related mutations, including IDH1, TERT, CIC, and FUBP1 mutations in 1p/19q codeleted patients, and glioblastoma-like signatures in 1p/19q intact patients. Aside from IDH1, potentially oncogenic/actionable mutations were variable, depicting wide molecular heterogeneity within oligodendroglial tumors. Conclusions: TMZ followed by HDC-ASCT can be safely administered to patients with newly diagnosed 1p/19q codeleted AO. This strategy was associated with promising PFS and OS, suggesting that a chemotherapy-based approach may delay the need for radiotherapy and radiation-related toxicities. Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odgmsk2017, accessed 6 January 2017. Clinicaltrials.gov registry: NCT00588523.  
  Address Memorial Sloan Kettering Cancer Center, New York, New York,USA; Northwestern Memorial Hospital, Chicago, Illinois, USA; NorthShore University, Evanston, Illinois,USA; University of Calgary, Calgary, Alberta, Canada; Massachusetts General Hospital, Boston, Massachusetts, USA; MD Anderson Cancer Center, Houston, Texas, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language (up) English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1522-8517 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28472509 Approved no  
  Call Number ref @ user @ Serial 96586  
Permanent link to this record
 

 
Author Oliva, C.R.; Zhang, W.; Langford, C.; Suto, M.J.; Griguer, C.E. url  doi
openurl 
  Title Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit Type Journal Article
  Year 2017 Publication Oncotarget Abbreviated Journal Oncotarget  
  Volume 8 Issue 23 Pages 37568-37583  
  Keywords chlorpromazine; cytochrome c oxidase; glioblastoma; inhibitor; stem cells  
  Abstract Patients with glioblastoma have one of the lowest overall survival rates among patients with cancer. Standard of care for patients with glioblastoma includes temozolomide and radiation therapy, yet 30% of patients do not respond to these treatments and nearly all glioblastoma tumors become resistant. Chlorpromazine is a United States Food and Drug Administration-approved phenothiazine widely used as a psychotropic in clinical practice. Recently, experimental evidence revealed the anti-proliferative activity of chlorpromazine against colon and brain tumors. Here, we used chemoresistant patient-derived glioma stem cells and chemoresistant human glioma cell lines to investigate the effects of chlorpromazine against chemoresistant glioma. Chlorpromazine selectively and significantly inhibited proliferation in chemoresistant glioma cells and glioma stem cells. Mechanistically, chlorpromazine inhibited cytochrome c oxidase (CcO, complex IV) activity from chemoresistant but not chemosensitive cells, without affecting other mitochondrial complexes. Notably, our previous studies revealed that the switch to chemoresistance in glioma cells is accompanied by a switch from the expression of CcO subunit 4 isoform 2 (COX4-2) to COX4-1. In this study, chlorpromazine induced cell cycle arrest selectively in glioma cells expressing COX4-1, and computer-simulated docking studies indicated that chlorpromazine binds more tightly to CcO expressing COX4-1 than to CcO expressing COX4-2. In orthotopic mouse brain tumor models, chlorpromazine treatment significantly increased the median overall survival of mice harboring chemoresistant tumors. These data indicate that chlorpromazine selectively inhibits the growth and proliferation of chemoresistant glioma cells expressing COX4-1. The feasibility of repositioning chlorpromazine for selectively treating chemoresistant glioma tumors should be further explored.  
  Address Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, 35294 Alabama, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language (up) English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1949-2553 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28455961 Approved no  
  Call Number ref @ user @ Serial 96587  
Permanent link to this record
 

 
Author Kim, M.Y.; Park, S.-J.; Shim, J.W.; Song, Y.J.; Yang, K.; Park, S.-J.; Heo, K. url  doi
openurl 
  Title Accumulation of low-dose BIX01294 promotes metastatic potential of U251 glioblastoma cells Type Journal Article
  Year 2017 Publication Oncology Letters Abbreviated Journal Oncol Lett  
  Volume 13 Issue 3 Pages 1767-1774  
  Keywords Bix01294; epithelial-mesenchymal transition; glioblastoma stem cells; metastasis  
  Abstract BIX01294 (Bix) is known to be a euchromatic histone-lysine N-methyltransferase 2 inhibitor and treatment with Bix suppresses cancer cell survival and proliferation. In the present study, it was observed that sequential treatment with low-dose Bix notably increases glioblastoma cell migration and metastasis. It was demonstrated that U251 cells sequentially treated with low-dose Bix exhibited induced characteristic changes in critical epithelial-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, beta-catenin and zinc finger protein SNAI2. Notably, sequential treatment with Bix also increased the expression of cancer stem cell-associated markers, including sex determining region Y-box 2, octamer-binding transcription factor 4 and cluster of differentiation 133. Neurosphere formation was significantly enhanced in cells sequentially treated with Bix, compared with control cells (control: P=0.011; single treatment of Bix, P=0.045). The results of the present study suggest that accumulation of low-dose Bix enhanced the migration and metastatic potential of glioblastoma cells by regulating EMT-associated gene expression, which may be the cause of the altered properties of glioblastoma stem cells.  
  Address Research Center, Dongnam Institute of Radiological and Medical Science (DIRAMS), Busan 619-953, Republic of Korea  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language (up) English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1792-1074 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28454322 Approved no  
  Call Number ref @ user @ Serial 96588  
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