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Glioblastoma treatment using perphenazine to block the subventricular zone’s tumor trophic functions

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Abstract

We present here a potential new treatment adjunct for glioblastoma. Building on murine studies, a series of papers appeared recently showing that therapeutic irradiation of the ipsilateral subventricular zone (SVZ) retards growth of more peripherally growing cortical glioblastomas in humans, suggesting a tumor trophic function for the SVZ. Further studies showed that SVZ cells migrate out towards a peripheral glioblastoma. Dopamine signaling through D3 subtype receptor indirectly drives this centrifugal migration in humans. Since psychiatry has several drugs with good D3 blocking attributes, such as fluphenazine, or perphenazine, we suggest that adding one of these D3 blocking drugs to current standard treatment of resection followed by temozolomide and irradiation might prolong survival by depriving glioblastoma of the trophic functions previously subserved by dopaminergic signaling on SVZ cells.

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References

  1. Efferth T, Ramirez T, Gebhart E, Halatsch ME (2004) Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774. Biochem Pharmacol 67(9):1689–1700

    Article  CAS  PubMed  Google Scholar 

  2. Kast RE, Boockvar JA, Brüning A et al (2013) A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget 4(4):502–530

    PubMed  Google Scholar 

  3. Kast RE (2010) Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct. Turk Neurosurg 20(4):425–429

    PubMed  Google Scholar 

  4. Azim K, Fiorelli R, Zweifel S, Hurtado-Chong A, Yoshikawa K, Slomianka L, Raineteau O (2012) 3-Dimensional examination of the adult mouse subventricular zone reveals lineage-specific microdomains. PLoS One 7(11):e49087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Young SZ, Taylor MM, Bordey A (2011) Neurotransmitters couple brain activity to subventricular zone neurogenesis. Eur J Neurosci 33(6):1123–1132

    Article  PubMed  PubMed Central  Google Scholar 

  6. Alvarez-Buylla A, Herrera DG, Wichterle H (2000) The subventricular zone: source of neuronal precursors for brain repair. Prog Brain Res 127:1–11

    Article  CAS  PubMed  Google Scholar 

  7. Young GS, Macklin EA, Setayesh K et al (2011) Longitudinal MRI evidence for decreased survival among periventricular glioblastoma. J Neurooncol 104(1):261–269

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sadahiro H, Yoshikawa K, Ideguchi M et al (2013) Pathological features of highly invasive glioma stem cells in a mouse xenograft model. Brain Tumor Pathol. doi:10.1007/s10014-013-0149-x

  9. Glantz M, Kesari S, Recht L, Fleischhack G, Van Horn A (2009) Understanding the origins of gliomas and developing novel therapies: cerebrospinal fluid and subventricular zone interplay. Semin Oncol 36(4 Suppl 2):S17–S24

    Article  CAS  PubMed  Google Scholar 

  10. Gleason D, Fallon JH, Guerra M, Liu JC, Bryant PJ (2008) Ependymal stem cells divide asymmetrically and transfer progeny into the subventricular zone when activated by injury. Neuroscience 156(1):81–88

    Article  CAS  PubMed  Google Scholar 

  11. Yang P, Arnold SA, Habas A, Hetman M, Hagg T (2008) Ciliary neurotrophic factor mediates dopamine D2 receptor-induced CNS neurogenesis in adult mice. J Neurosci 28(9):2231–2241

    Article  CAS  PubMed  Google Scholar 

  12. Muñoz DM, Guha A (2011) Mouse models to interrogate the implications of the differentiation status in the ontogeny of gliomas. Oncotarget 2(8):590–598

    PubMed  Google Scholar 

  13. Najbauer J, Huszthy PC, Barish ME et al (2012) Cellular host responses to gliomas. PLoS One 7(4):e35150. doi:10.1371/journal.pone.0035150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tchoghandjian A, Baeza-Kallee N, Beclin C et al (2012) Cortical and subventricular zone glioblastoma-derived stem-like cells display different molecular profiles and differential in vitro and in vivo properties. Ann Surg Oncol 19(Suppl3):S608–S619. doi:10.1245/s10434-011-2093-5

    Article  PubMed  Google Scholar 

  15. Kroonen J, Nassen J, Boulanger YG et al (2011) Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection. Int J Cancer 129(3):574–585

    Article  CAS  PubMed  Google Scholar 

  16. Winner B, Desplats P, Hagl C et al (2009) Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model. Exp Neurol 219(2):543–552

    Article  CAS  PubMed  Google Scholar 

  17. Kim Y, Wang WZ, Comte I et al (2010) Dopamine stimulation of postnatal murine subventricular zone neurogenesis via the D3 receptor. J Neurochem 114(3):750–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen L, Guerrero-Cazares H, Ye X et al (2013) Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection. Int J Radiat Oncol Biol Phys 86(4):616–622

    Article  PubMed  Google Scholar 

  19. Gupta T, Nair V, Paul SN et al (2012) Can irradiation of potential cancer stem-cell niche in the subventricular zone influence survival in patients with newly diagnosed glioblastoma? J Neurooncol 109(1):195–203

    Article  PubMed  Google Scholar 

  20. Evers P, Lee PP, DeMarco J et al (2010) Irradiation of the potential cancer stem cell niches in the adult brain improves progression-free survival of patients with malignant glioma. BMC Cancer 10:384

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lee P, Eppinga W, Lagerwaard F et al (2013) Evaluation of high ipsilateral subventricular zone radiation therapy dose in glioblastoma: a pooled analysis. Int J Radiat Oncol Biol Phys 86(4):609–615

    Article  PubMed  Google Scholar 

  22. Ellingson BM, Lai A, Harris RJ et al (2013) Probabilistic radiographic atlas of glioblastoma phenotypes. AJNR Am J Neuroradiol 34(3):533–540

    Article  CAS  PubMed  Google Scholar 

  23. Ellingson BM, Cloughesy TF, Pope WB et al (2012) Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas. Neuroimage 59(2):908–916

    Article  CAS  PubMed  Google Scholar 

  24. Kappadakunnel M, Eskin A, Dong J et al (2010) Stem cell associated gene expression in glioblastoma multiforme: relationship to survival and the subventricular zone. J Neurooncol 96(3):359–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lim DA, Cha S, Mayo MC et al (2007) Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro Oncol 9(4):424–429

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lao CL, Lu CS, Chen JC (2013) Dopamine D(3) receptor activation promotes neural stem/progenitor cell proliferation through AKT and ERK1/2 pathways and expands type-B and -C cells in adult subventricular zone. Glia 61(4):475–489

    Article  PubMed  Google Scholar 

  27. Baker SA, Baker KA, Hagg T (2005) D3 dopamine receptors do not regulate neurogenesis in the subventricular zone of adult mice. Neurobiol Dis 18(3):523–527

    Article  CAS  PubMed  Google Scholar 

  28. Merlo S, Canonico PL, Sortino MA (2011) Distinct effects of pramipexole on the proliferation of adult mouse sub-ventricular zone-derived cells and the appearance of a neuronal phenotype. Neuropharmacology 60(6):892–900

    Article  CAS  PubMed  Google Scholar 

  29. Coronas V, Bantubungi K, Fombonne J, Krantic S, Schiffmann SN, Roger M (2004) Dopamine D3 receptor stimulation promotes the proliferation of cells derived from the post-natal subventricular zone. J Neurochem 91(6):1292–1301

    Article  CAS  PubMed  Google Scholar 

  30. O’Keeffe GC, Tyers P, Aarsland D, Dalley JW, Barker RA, Caldwell MA (2009) Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF. Proc Natl Acad Sci USA 106(21):8754–8759

    Article  PubMed  Google Scholar 

  31. O’Keeffe GC, Barker RA (2011) Dopamine stimulates epidermal growth factor release from adult neural precursor cells derived from the subventricular zone by a disintegrin and metalloprotease. Neuroreport 22(18):956–958

    Article  PubMed  Google Scholar 

  32. Hartung B, Wada M, Laux G, Leucht S (2005) Perphenazine for schizophrenia. Cochrane Database Syst Rev 25(1):CD003443

    Google Scholar 

  33. Addington DE, Mohamed S, Rosenheck RA et al (2011) Impact of second-generation antipsychotics and perphenazine on depressive symptoms in a randomized trial of treatment for chronic schizophrenia. J Clin Psychiatry 72(1):75–80. doi:10.4088/JCP.09m05258gre

    Article  CAS  PubMed  Google Scholar 

  34. Schnabel A, Eberhart LH, Muellenbach R, Morin AM, Roewer N, Kranke P (2010) Efficacy of perphenazine to prevent postoperative nausea and vomiting: a quantitative systematic review. Eur J Anaesthesiol 27(12):1044–1051

    Article  CAS  PubMed  Google Scholar 

  35. Anton RF Jr, Burch EA Jr (1993) Response of psychotic depression subtypes to pharmacotherapy. J Affect Disord 28(2):125–131

    Article  PubMed  Google Scholar 

  36. Tadori Y, Forbes RA, McQuade RD, Kikuchi T (2011) Functional potencies of dopamine agonists and antagonists at human dopamine D2 and D3 receptors. Eur J Pharmacol 666(1–3):43–52

    Article  CAS  PubMed  Google Scholar 

  37. Glass R, Synowitz M, Kronenberg G et al (2005) Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 25(10):2637–2646

    Article  CAS  PubMed  Google Scholar 

  38. Walzlein JH, Synowitz M, Engels B et al (2008) The antitumorigenic response of neural precursors depends on subventricular proliferation and age. Stem Cells 26(11):2945–2954

    Article  CAS  PubMed  Google Scholar 

  39. Maggio R, Millan MJ (2010) Dopamine D2–D3 receptor heteromers: pharmacological properties and therapeutic significance. Curr Opin Pharmacol 10(1):100–107

    Article  CAS  PubMed  Google Scholar 

  40. Pou C, Mannoury la Cour C, Stoddart LA, Millan MJ, Milligan G (2012) Functional homomers and heteromers of dopamine D2L and D3 receptors co-exist at the cell surface. J Biol Chem 287(12):8864–8878

    Article  CAS  PubMed  Google Scholar 

  41. Vilner BJ, Bowen WD (1993) Sigma receptor-active neuroleptics are cytotoxic to C6 glioma cells in culture. Eur J Pharmacol 244(2):199–201

    Article  CAS  PubMed  Google Scholar 

  42. Kast RE (2007) Glioblastoma: looking at the currently marketed sigma-1 agonists and antagonists. Neoplasia 9(8):689

    Article  PubMed  PubMed Central  Google Scholar 

  43. Mégalizzi V, Decaestecker C, Debeir O et al (2009) Screening of anti-glioma effects induced by sigma-1 receptor ligands: potential new use for old anti-psychiatric medicines. Eur J Cancer 45(16):2893–2905

    Article  PubMed  Google Scholar 

  44. Betizeau M, Cortay V, Patti D et al (2013) Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate. Neuron 80(2):442–457. doi:10.1016/j.neuron.2013.09.032

    Article  CAS  PubMed  Google Scholar 

  45. Gonzales-Roybal G, Lim DA (2013) Chromatin-based epigenetics of adult subventricular zone neural stem cells. Front Genet 4:194

    Article  PubMed  PubMed Central  Google Scholar 

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Conflict of interest

None of the authors has conflict of interest to declare.

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Authors and Affiliations

  1. IIAIGC Study Center, 22 Church Street, Burlington, VT, 05401, USA

    R. E. Kast

  2. UCLA Brain Tumor Imaging Laboratory, Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA

    B. M. Ellingson

  3. Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

    C. Marosi

  4. Department of Neurosurgery, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany

    M.-E. Halatsch

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  1. R. E. Kast
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  2. B. M. Ellingson
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  3. C. Marosi
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  4. M.-E. Halatsch
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Correspondence to R. E. Kast.

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Kast, R.E., Ellingson, B.M., Marosi, C. et al. Glioblastoma treatment using perphenazine to block the subventricular zone’s tumor trophic functions. J Neurooncol 116, 207–212 (2014). https://doi.org/10.1007/s11060-013-1308-y

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  • DOI: https://doi.org/10.1007/s11060-013-1308-y

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