Skip to main content

Advertisement

SpringerLink
Log in

Drug Repurposing in Medulloblastoma: Challenges and Recommendations

  • Neuro-oncology (GJ Lesser, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Medulloblastoma is the most frequently diagnosed primary malignant brain tumor among children. Currently available therapeutic strategies are based on surgical resection, chemotherapy, and/or radiotherapy. However, majority of patients quickly develop therapeutic resistance and are often left with long-term therapy-related side effects and sequelae. Therefore, there remains a dire need to develop more effective therapeutics to overcome the acquired resistance to currently available therapies. Unfortunately, the process of developing novel anti-neoplastic drugs from bench to bedside is highly time-consuming and very expensive. A wide range of drugs that are already in clinical use for treating non-cancerous diseases might commonly target tumor-associated signaling pathways as well and hence be of interest in treating different cancers. This is referred to as drug repurposing or repositioning. In medulloblastoma, drug repurposing has recently gained a remarkable interest as an alternative therapy to overcome therapy resistance, wherein existing non-tumor drugs are being tested for their potential anti-neoplastic effects outside the scope of their original use.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kumar LP, Deepa SFAJ, Moinca I, Suresh P, Naidu KVJR. Medulloblastoma: a common pediatric tumor: prognostic factors and predictors of outcome. Asian J Neurosurg. 2015;10(1):50. https://doi.org/10.4103/1793-5482.151516.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Parkes J, Hendricks M, Ssenyonga P, Mugamba J, Molyneux E, Schouten-van Meeteren A, et al. SIOP PODC adapted treatment recommendations for standard-risk medulloblastoma in low and middle income settings. Pediatric Blood & Cancer. 2015;62(4):553–64. https://doi.org/10.1002/pbc.25313.

    Article  Google Scholar 

  3. Bahmad HF, Poppiti RJ (2020) Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets. Journal of clinical pathology 73 (5):243-249. doi:10.1136/jclinpath-2019-206246. Reason: Comprehensive review providing a synopsis of the novel therapeutic approaches that specifically target medulloblastoma cancer stem cells to attain enhanced anti-tumorous effects and overcome therapy resistance.

  4. Millard NE, De Braganca KC. Medulloblastoma. J Child Neurol. 2016;31(12):1341–53. https://doi.org/10.1177/0883073815600866.

    Article  PubMed  Google Scholar 

  5. Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A. Medulloblastoma: from molecular pathology to therapy. Clin Cancer Res. 2008;14(4):971–6. https://doi.org/10.1158/1078-0432.CCR-07-2072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gilbertson RJ, Ellison DW. The origins of medulloblastoma subtypes. Annual Review of Pathology: Mechanisms of Disease. 2008;3(1):341–65. https://doi.org/10.1146/annurev.pathmechdis.3.121806.151518.

    Article  CAS  Google Scholar 

  7. Yokota N, Aruga J, Takai S, Yamada K, Hamazaki M, Iwase T, et al. Predominant expression of human Zic in cerebellar granule cell lineage and medulloblastoma. Cancer Research. 1996;56(2):377.

    CAS  PubMed  Google Scholar 

  8. Behesti H, Marino S. Cerebellar granule cells: insights into proliferation, differentiation, and role in medulloblastoma pathogenesis. The International Journal of Biochemistry & Cell Biology. 2009;41(3):435–45. https://doi.org/10.1016/j.biocel.2008.06.017.

    Article  CAS  Google Scholar 

  9. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS (2018) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro Oncol 20 (suppl_4):iv1-iv86. doi:https://doi.org/10.1093/neuonc/noy131

  10. Esbenshade AJ, Kocak M, Hershon L, Rousseau P, Decarie J-C, Shaw S, Burger P, Friedman HS, Gajjar A, Moghrabi A (2017) A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): a report from the Children’s Oncology Group. Pediatric blood & cancer 64 (6):10.1002/pbc.26373. doi:https://doi.org/10.1002/pbc.26373

  11. von Bueren AO, Kortmann R-D, von Hoff K, Friedrich C, Mynarek M, Müller K, Goschzik T, zur Mühlen A, Gerber N, Warmuth-Metz M, Soerensen N, Deinlein F, Benesch M, Zwiener I, Kwiecien R, Faldum A, Bode U, Fleischhack G, Hovestadt V, Kool M, Jones D, Northcott P, Kuehl J, Pfister S, Pietsch T, Rutkowski S (2016) Treatment of children and adolescents with metastatic medulloblastoma and prognostic relevance of clinical and biologic parameters. Journal of Clinical Oncology 34 (34):4151-4160. doi:https://doi.org/10.1200/JCO.2016.67.2428

  12. Muzumdar D, Deshpande A, Kumar R, Sharma A, Goel N, Dange N, et al. Medulloblastoma in childhood-King Edward Memorial hospital surgical experience and review: comparative analysis of the case series of 365 patients. J Pediatr Neurosci. 2011;6(Suppl 1):S78–85. https://doi.org/10.4103/1817-1745.85717.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rajagopal R, Abd-Ghafar S, Ganesan D, Bustam Mainudin AZ, Wong KT, Ramli N, et al. Challenges of treating childhood medulloblastoma in a country with limited resources: 20 years of experience at a single tertiary center in Malaysia. J Glob Oncol. 2016;3(2):143–56. https://doi.org/10.1200/JGO.2015.002659.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109. https://doi.org/10.1007/s00401-007-0243-4.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Crawford JR, MacDonald TJ, Packer RJ. Medulloblastoma in childhood: new biological advances. The Lancet Neurology. 2007;6(12):1073–85. https://doi.org/10.1016/s1474-4422(07)70289-2.

    Article  CAS  PubMed  Google Scholar 

  16. Giangaspero F, Perilongo G, Fondelli MP, Brisigotti M, Carollo C, Burnelli R, et al. Medulloblastoma with extensive nodularity: a variant with favorable prognosis. Journal of Neurosurgery. 1999;91(6):971–7. https://doi.org/10.3171/jns.1999.91.6.0971.

    Article  CAS  PubMed  Google Scholar 

  17. Lamont JM, McManamy CS, Pearson AD, Clifford SC, Ellison DW. Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clinical Cancer Research. 2004;10(16):5482. https://doi.org/10.1158/1078-0432.CCR-03-0721.

    Article  CAS  PubMed  Google Scholar 

  18. Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, et al. The WHO Classification of tumors of the nervous system. Journal of Neuropathology & Experimental Neurology. 2002;61(3):215–25. https://doi.org/10.1093/jnen/61.3.215.

    Article  Google Scholar 

  19. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. World health organization classification of tumours of the central nervous system, vol. 1. Revised. 4th ed. Lyon: IARC Press; 2016.

    Google Scholar 

  20. Kawauchi D, Robinson G, Uziel T, Gibson P, Rehg J, Gao C, et al. A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer cell. 2012;21(2):168–80. https://doi.org/10.1016/j.ccr.2011.12.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, et al. An animal model of MYC-driven medulloblastoma. Cancer cell. 2012;21(2):155–67. https://doi.org/10.1016/j.ccr.2011.12.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Swartling FJ, Grimmer MR, Hackett CS, Northcott PA, Fan QW, Goldenberg DD, et al. Pleiotropic role for MYCN in medulloblastoma. Genes & development. 2010;24(10):1059–72. https://doi.org/10.1101/gad.1907510.

    Article  CAS  Google Scholar 

  23. Swartling FJ, Savov V, Persson AI, Chen J, Hackett CS, Northcott PA, et al. Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. Cancer cell. 2012;21(5):601–13. https://doi.org/10.1016/j.ccr.2012.04.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Menyhárt O, Giangaspero F, Győrffy B (2019) Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas. Journal of Hematology & Oncology 12 (1):29. doi:10.1186/s13045-019-0712-y. Reason: Review delineating the molecular aberrations involved in MB tumorigenesis, particularly groups 3 and 4, paving the way to identifying potential therapeutic targets for drug repurposing in medulloblastoma.

  25. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho Y-J, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–72. https://doi.org/10.1007/s00401-011-0922-z.

    Article  CAS  PubMed  Google Scholar 

  26. Mir SE, Smits M, Biesmans D, Julsing M, Bugiani M, Aronica E, Kaspers GJL, Cloos J, Würdinger T, Hulleman E (2017) Trimethylation of H3K27 during human cerebellar development in relation to medulloblastoma. Oncotarget 8 (45):78978-78988. doi:10.18632/oncotarget.20741

  27. Robbins CJ, Bou-Dargham MJ, Sanchez K, Rosen MC, Sang Q-XA. Decoding somatic driver gene mutations and affected signaling pathways in human medulloblastoma subgroups. J Cancer. 2018;9(24):4596–610. https://doi.org/10.7150/jca.27993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fattet S, Haberler C, Legoix P, Varlet P, Lellouch-Tubiana A, Lair S, et al. Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics. The Journal of pathology. 2009;218(1):86–94. https://doi.org/10.1002/path.2514.

    Article  CAS  PubMed  Google Scholar 

  29. Yokota N, Nishizawa S Fau - Ohta S, Ohta S Fau - Date H, Date H Fau - Sugimura H, Sugimura H Fau - Namba H, Namba H Fau - Maekawa M, Maekawa M Role of Wnt pathway in medulloblastoma oncogenesis. (0020-7136 (Print))

  30. Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol. 2006;24(12):1924–31. https://doi.org/10.1200/jco.2005.04.4974.

    Article  CAS  PubMed  Google Scholar 

  31. Clifford SC, Lusher ME, Lindsey JC, Langdon JA, Gilbertson RJ, Straughton D, et al. Wnt/wingless pathway activation and chromosome 6 loss characterise a distinct molecular sub-group of medulloblastomas associated with a favourable prognosis. Cell Cycle. 2006;5(22):2666–70. https://doi.org/10.4161/cc.5.22.3446.

    Article  CAS  PubMed  Google Scholar 

  32. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29(11):1408–14. https://doi.org/10.1200/JCO.2009.27.4324.

    Article  PubMed  Google Scholar 

  33. Cambruzzi E. Medulloblastoma, WNT-activated/SHH-activated: clinical impact of molecular analysis and histogenetic evaluation. Child's Nervous System. 2018;34(5):809–15. https://doi.org/10.1007/s00381-018-3765-2.

    Article  PubMed  Google Scholar 

  34. Higdon R, Kala J, Wilkins D, Yan JF, Sethi MK, Lin L, et al. Integrated proteomic and transcriptomic-based approaches to identifying signature biomarkers and pathways for elucidation of Daoy and UW228 subtypes. Proteomes. 2017;5(1):5. https://doi.org/10.3390/proteomes5010005.

    Article  CAS  PubMed Central  Google Scholar 

  35. Northcott PA, Shih DJH, Remke M, Cho Y-J, Kool M, Hawkins C, et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123(4):615–26. https://doi.org/10.1007/s00401-011-0899-7.

    Article  CAS  PubMed  Google Scholar 

  36. Taylor MD, Liu L, Raffel C, C-c H, Mainprize TG, Zhang X, et al. Mutations in SUFU predispose to medulloblastoma. Nature Genetics. 2002;31(3):306–10. https://doi.org/10.1038/ng916.

    Article  CAS  PubMed  Google Scholar 

  37. Menyhárt O, Győrffy B. Principles of tumorigenesis and emerging molecular drivers of SHH-activated medulloblastomas. Ann Clin Transl Neurol. 2019;6(5):990–1005. https://doi.org/10.1002/acn3.762.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Roussel MF, Robinson GW. Role of MYC in medulloblastoma. Cold Spring Harb Perspect Med. 2013;3(11):a014308. https://doi.org/10.1101/cshperspect.a014308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tao R, Murad N, Xu Z, Zhang P, Okonechnikov K, Kool M, et al. MYC drives group 3 medulloblastoma through transformation of Sox2(+) astrocyte progenitor cells. Cancer research. 2019;79(8):1967–80. https://doi.org/10.1158/0008-5472.CAN-18-1787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sengupta S, Pomeranz Krummel D, Pomeroy S (2017) The evolution of medulloblastoma therapy to personalized medicine. F1000Res 6:490-490. doi:10.12688/f1000research.10859.1

  41. Park AK, Lee JY, Cheong H, Ramaswamy V, Park S-H, Kool M, et al. Subgroup-specific prognostic signaling and metabolic pathways in pediatric medulloblastoma. BMC Cancer. 2019;19(1):571. https://doi.org/10.1186/s12885-019-5742-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Thomas A, Noël G. Medulloblastoma: optimizing care with a multidisciplinary approach. J Multidiscip Healthc. 2019;12:335–47. https://doi.org/10.2147/JMDH.S167808.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rutkowski S, Gerber NU, von Hoff K, Gnekow A, Bode U, Graf N, Berthold F, Henze G, Wolff JEA, Warmuth-Metz M, Soerensen N, Emser A, Ottensmeier H, Deinlein F, Schlegel P-G, Kortmann R-D, Pietsch T, Kuehl J, German Pediatric Brain Tumor Study G. Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol. 2009;11(2):201–10. https://doi.org/10.1215/15228517-2008-084.

    Article  CAS  Google Scholar 

  44. Srinivasan VM, Ghali MGZ, North RY, Boghani Z, Hansen D, Lam S. Modern management of medulloblastoma: Molecular classification, outcomes, and the role of surgery. Surg Neurol Int. 2016;7(Suppl 44):S1135–41. https://doi.org/10.4103/2152-7806.196922.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pols S, van Veelen MLC, Aarsen FK, Gonzalez Candel A, Catsman-Berrevoets CE. Risk factors for development of postoperative cerebellar mutism syndrome in children after medulloblastoma surgery. Journal of neurosurgery Pediatrics. 2017;20(1):35–41. https://doi.org/10.3171/2017.2.peds16605.

    Article  PubMed  Google Scholar 

  46. Giambelli C, Fei DL, Wang H, Robbins DJ. Repurposing an old anti-fungal drug as a Hedgehog inhibitor. Protein & Cell. 2010;1(5):417–8. https://doi.org/10.1007/s13238-010-0063-5.

    Article  Google Scholar 

  47. Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer cell. 2010;17(4):388–99. https://doi.org/10.1016/j.ccr.2010.02.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers P, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol. 2005;23(24):5511–9. https://doi.org/10.1200/jco.2005.00.703.

    Article  PubMed  Google Scholar 

  49. Ivanov DP, Coyle B, Walker DA, Grabowska AM. In vitro models of medulloblastoma: Choosing the right tool for the job. Journal of Biotechnology. 2016;236:10–25. https://doi.org/10.1016/j.jbiotec.2016.07.028.

    Article  CAS  PubMed  Google Scholar 

  50. Duffner Pk Fau - Cohen ME, Cohen Me Fau - Thomas PR, Thomas Pr Fau - Sinks LF, Sinks Lf Fau - Freeman AI, Freeman AI Combination chemotherapy in recurrent medulloblastoma. (0008-543X (Print))

  51. Mollashahi B, Aghamaleki FS, Movafagh A (2019) The roles of miRNAs in medulloblastoma: a systematic review. J Cancer Prev 24 (2):79-90. doi:10.15430/JCP.2019.24.2.79

  52. Bahmad HF, Chamaa F, Assi S, Chalhoub RM, Abou-Antoun T, Abou-Kheir W. Cancer stem cells in neuroblastoma: expanding the therapeutic frontier. Frontiers in molecular neuroscience. 2019;12:131. https://doi.org/10.3389/fnmol.2019.00131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ramaswamy V, Remke M, Bouffet E, Faria CC, Perreault S, Cho Y-J, et al. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol. 2013;14(12):1200–7. https://doi.org/10.1016/S1470-2045(13)70449-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bahmad HF, Elajami MK, El Zarif T, Bou-Gharios J, Abou-Antoun T, Abou-Kheir W (2020) Drug repurposing towards targeting cancer stem cells in pediatric brain tumors. Cancer metastasis reviews 39 (1):127-148. doi:10.1007/s10555-019-09840-2. Reason: review elucidating the drug repurposing methodologies that have been used in pediatric brain tumors and how this selective compilation of approaches could elevate drug repurposing to the next level.

  55. Prasad V, Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval. JAMA Intern Med. 2017;177(11):1569–75. https://doi.org/10.1001/jamainternmed.2017.3601.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wu CH, Bai LY, Tsai MH, Chu PC, Chiu CF, Chen MY, et al. Pharmacological exploitation of the phenothiazine antipsychotics to develop novel antitumor agents-a drug repurposing strategy. Sci Rep. 2016;6:27540. https://doi.org/10.1038/srep27540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Aggarwal S, Verma SS, Aggarwal S, Gupta SC. Drug repurposing for breast cancer therapy: old weapon for new battle. Seminars in Cancer Biology. 2019. https://doi.org/10.1016/j.semcancer.2019.09.012.

  58. Giordano SH, Lin YL, Kuo YF, Hortobagyi GN, Goodwin JS. Decline in the use of anthracyclines for breast cancer. J Clin Oncol. 2012;30(18):2232–9. https://doi.org/10.1200/jco.2011.40.1273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nabhan C, Byrtek M, Rai A, Dawson K, Zhou X, Link BK, et al. Disease characteristics, treatment patterns, prognosis, outcomes and lymphoma-related mortality in elderly follicular lymphoma in the United States. Br J Haematol. 2015;170(1):85–95. https://doi.org/10.1111/bjh.13399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chihara D, Westin JR, Oki Y, Ahmed MA, Do B, Fayad LE, et al. Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma. Cancer. 2016;122(20):3145–51. https://doi.org/10.1002/cncr.30173.

    Article  CAS  PubMed  Google Scholar 

  61. Pasquier E, Ciccolini J, Carre M, Giacometti S, Fanciullino R, Pouchy C, Montero MP, Serdjebi C, Kavallaris M, André N (2011) Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget 2 (10):797-809. doi:10.18632/oncotarget.343

  62. Dubus E, Ijjaali I, Barberan O, Petitet F. Drug repositioning using in silico compound profiling. Future Medicinal Chemistry. 2009;1(9):1723–36. https://doi.org/10.4155/fmc.09.123.

    Article  CAS  PubMed  Google Scholar 

  63. Smith MA, Seibel NL, Altekruse SF, Ries LA, Melbert DL, O'Leary M, et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol. 2010;28(15):2625–34. https://doi.org/10.1200/JCO.2009.27.0421.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Brinkman TM, Krasin MJ, Liu W, Armstrong GT, Ojha RP, Sadighi ZS, et al. Long-term neurocognitive functioning and social attainment in adult survivors of pediatric CNS tumors: results from the St Jude Lifetime Cohort Study. J Clin Oncol. 2016;34(12):1358–67. https://doi.org/10.1200/JCO.2015.62.2589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Saker Z, Bahmad HF, Fares Y, Al Najjar Z, Saad M, Harati H, et al. Prognostic impact of adenylyl cyclase-associated protein 2 (CAP2) in glioma: a clinicopathological study. Heliyon. 2020;6(1):e03236. https://doi.org/10.1016/j.heliyon.2020.e03236.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Janzer RC, Raff MC. Astrocytes induce blood–brain barrier properties in endothelial cells. Nature. 1987;325(6101):253–7. https://doi.org/10.1038/325253a0.

    Article  CAS  PubMed  Google Scholar 

  67. Biegel D, Spencer DD, Pachter JS. Isolation and culture of human brain microvessel endothelial cells for the study of blood-brain barrier properties in vitro. Brain Res. 1995;692(1-2):183–9. https://doi.org/10.1016/0006-8993(95)00511-n.

    Article  CAS  PubMed  Google Scholar 

  68. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. Mfsd2a is critical for the formation and function of the blood–brain barrier. Nature. 2014;509(7501):507–11. https://doi.org/10.1038/nature13324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Thorsen F, Fite B, Mahakian LM, Seo JW, Qin S, Harrison V, et al. Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases. J Control Release. 2013;172(3):812–22. https://doi.org/10.1016/j.jconrel.2013.10.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Carbonell WS, Ansorge O, Sibson N, Muschel R. The vascular basement membrane as “soil” in brain metastasis. PLOS ONE. 2009;4(6):e5857. https://doi.org/10.1371/journal.pone.0005857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Palmieri D, Chambers AF, Felding-Habermann B, Huang S, Steeg PS. The biology of metastasis to a sanctuary site. Clinical Cancer Research. 2007;13(6):1656–62. https://doi.org/10.1158/1078-0432.ccr-06-2659.

    Article  CAS  PubMed  Google Scholar 

  72. Kakee A, Terasaki T, Sugiyama Y. Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier. J Pharmacol Exp Ther. 1996;277(3):1550–9.

    CAS  PubMed  Google Scholar 

  73. Wager TT, Hou X, Verhoest PR, Villalobos A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chemical Neuroscience. 2010;1(6):435–49. https://doi.org/10.1021/cn100008c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lilius TO, Blomqvist K, Hauglund NL, Liu G, Stæger FF, Bærentzen S, Du T, Ahlström F, Backman JT, Kalso EA (2019) Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs.

  75. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4 (147):147ra111. 2012. https://doi.org/10.1126/scitranslmed.3003748.

  76. Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488(7409):100–5. https://doi.org/10.1038/nature11284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Phoenix TN, Patmore DM, Boop S, Boulos N, Jacus MO, Patel YT, et al. Medulloblastoma genotype dictates blood brain barrier phenotype. Cancer cell. 2016;29(4):508–22. https://doi.org/10.1016/j.ccell.2016.03.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–78. https://doi.org/10.1016/S0140-6736(05)67394-1.

    Article  CAS  PubMed  Google Scholar 

  79. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. New England Journal of Medicine. 2012;367(19):1792–802. https://doi.org/10.1056/NEJMoa1201735.

    Article  CAS  Google Scholar 

  80. Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis. J Clin Invest. 1987;80(6):1692–7. https://doi.org/10.1172/JCI113259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Endo A, Tsujita Y, Kuroda M, Tanzawa K. Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Eur J Biochem. 1977;77(1):31–6. https://doi.org/10.1111/j.1432-1033.1977.tb11637.x.

    Article  CAS  PubMed  Google Scholar 

  82. Tobert JA, Hitzenberger G, Kukovetz WR, Holmes IB, Jones KH. Rapid and substantial lowering of human serum cholesterol by mevinolin (MK-803), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase. Atherosclerosis. 1982;41(1):61–5. https://doi.org/10.1016/0021-9150(82)90070-3.

    Article  CAS  PubMed  Google Scholar 

  83. Wang W, Macaulay RJ. Mevalonate prevents lovastatin-induced apoptosis in medulloblastoma cell lines. Can J Neurol Sci. 1999;26(4):305–10. https://doi.org/10.1017/s0317167100000433.

    Article  CAS  PubMed  Google Scholar 

  84. Tanaka T, Tatsuno I, Uchida D, Moroo I, Morio H, Nakamura S, et al. Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition. Journal of Neuroscience. 2000;20(8):2852–9.

    Article  CAS  Google Scholar 

  85. Dimitroulakos J, Yeger H. HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expressing cells. Nat Med. 1996;2(3):326–33. https://doi.org/10.1038/nm0396-326.

    Article  CAS  PubMed  Google Scholar 

  86. Jones KD, Couldwell WT, Hinton DR, Su Y, He S, Anker L, et al. Lovastatin induces growth inhibition and apoptosis in human malignant glioma cells. Biochem Biophys Res Commun. 1994;205(3):1681–7. https://doi.org/10.1006/bbrc.1994.2861.

    Article  CAS  PubMed  Google Scholar 

  87. Miller AC, Samid D. Tumor resistance to oxidative stress: association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21ras isoprenylation. Int J Cancer. 1995;60(2):249–54. https://doi.org/10.1002/ijc.2910600220.

    Article  CAS  PubMed  Google Scholar 

  88. Macaulay RJ, Wang W, Dimitroulakos J, Becker LE, Yeger H. Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro. J Neurooncol. 1999;42(1):1–11. https://doi.org/10.1023/a:1006164406202.

    Article  CAS  PubMed  Google Scholar 

  89. Wang W, Macaulay RJ. Cell-cycle gene expression in lovastatin-induced medulloblastoma apoptosis. Can J Neurol Sci. 2003;30(4):349–57. https://doi.org/10.1017/s0317167100003061.

    Article  PubMed  Google Scholar 

  90. Takwi AA, Li Y, Becker Buscaglia LE, Zhang J, Choudhury S, Park AK, et al. A statin-regulated microRNA represses human c-Myc expression and function. EMBO Mol Med. 2012;4(9):896–909. https://doi.org/10.1002/emmm.201101045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sheikholeslami K, Ali Sher A, Lockman S, Kroft D, Ganjibakhsh M, Nejati-Koshki K, et al. Simvastatin induces apoptosis in medulloblastoma brain tumor cells via mevalonate cascade prenylation substrates. Cancers (Basel). 2019;11(7). https://doi.org/10.3390/cancers11070994.

  92. Gordon RE, Zhang L, Peri S, Kuo YM, Du F, Egleston BL, et al. Statins synergize with hedgehog pathway inhibitors for treatment of medulloblastoma. Clin Cancer Res. 2018;24(6):1375–88. https://doi.org/10.1158/1078-0432.CCR-17-2923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ling H, Luoma JT, Hilleman D. A review of currently available fenofibrate and fenofibric acid formulations. Cardiol Res. 2013;4(2):47–55. https://doi.org/10.4021/cr270w.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Urbanska K, Pannizzo P, Grabacka M, Croul S, Del Valle L, Khalili K, et al. Activation of PPARalpha inhibits IGF-I-mediated growth and survival responses in medulloblastoma cell lines. Int J Cancer. 2008;123(5):1015–24. https://doi.org/10.1002/ijc.23588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schwinger RH, Bohm M, Erdmann E. Effectiveness of cardiac glycosides in human myocardium with and without “downregulated” beta-adrenoceptors. J Cardiovasc Pharmacol. 1990;15(5):692–7. https://doi.org/10.1097/00005344-199005000-00002.

    Article  CAS  PubMed  Google Scholar 

  96. Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs. 2001;12(5):475–83. https://doi.org/10.1097/00001813-200106000-00009.

    Article  CAS  PubMed  Google Scholar 

  97. Perne A, Muellner MK, Steinrueck M, Craig-Mueller N, Mayerhofer J, Schwarzinger I, et al. Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis. PLoS One. 2009;4(12):e8292. https://doi.org/10.1371/journal.pone.0008292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Osman MH, Farrag E, Selim M, Osman MS, Hasanine A, Selim A. Cardiac glycosides use and the risk and mortality of cancer; systematic review and meta-analysis of observational studies. PLoS One. 2017;12(6):e0178611. https://doi.org/10.1371/journal.pone.0178611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kometiani P, Liu L, Askari A. Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. Mol Pharmacol. 2005;67(3):929–36. https://doi.org/10.1124/mol.104.007302.

    Article  CAS  PubMed  Google Scholar 

  100. Huang L, Garrett Injac S, Cui K, Braun F, Lin Q, Du Y, Zhang H, Kogiso M, Lindsay H, Zhao S, Baxter P, Adekunle A, Man T-K, Zhao H, Li X-N, Lau CC, Wong STC (2018) Systems biology-based drug repositioning identifies digoxin as a potential therapy for groups 3 and 4 medulloblastoma. Science translational medicine 10 (464):eaat0150. doi:https://doi.org/10.1126/scitranslmed.aat0150

  101. Wolle D, Lee SJ, Li Z, Litan A, Barwe SP, Langhans SA. Inhibition of epidermal growth factor signaling by the cardiac glycoside ouabain in medulloblastoma. Cancer Med. 2014;3(5):1146–58. https://doi.org/10.1002/cam4.314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Schmidt WF, Huber KR, Ettinger RS, Neuberg RW. Antiproliferative effect of verapamil alone on brain tumor cells in vitro. Cancer Res. 1988;48(13):3617–21.

    CAS  PubMed  Google Scholar 

  103. Ingram WJ, Crowther LM, Little EB, Freeman R, Harliwong I, Veleva D, et al. ABC transporter activity linked to radiation resistance and molecular subtype in pediatric medulloblastoma. Exp Hematol Oncol. 2013;2(1):26. https://doi.org/10.1186/2162-3619-2-26.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Chen Y, Bai N, Bi J, Zhang J, Li X, Zhang L, et al. Propranolol induces apoptosis in endothelial cells by inhibiting AKt and ERK phosphorylation and MAPK signaling pathway. International Journal of Clinical and Experimental Medicine. 2017;10:13167–73.

    Google Scholar 

  105. Annabi B, Vaillancourt-Jean E, Weil AG, Beliveau R. Pharmacological targeting of beta-adrenergic receptor functions abrogates NF-kappaB signaling and MMP-9 secretion in medulloblastoma cells. Onco Targets Ther. 2010;3:219–26. https://doi.org/10.2147/OTT.S14503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Smout MJ, Kotze AC, McCarthy JS, Loukas A. A novel high throughput assay for anthelmintic drug screening and resistance diagnosis by real-time monitoring of parasite motility. PLoS Negl Trop Dis. 2010;4(11):e885. https://doi.org/10.1371/journal.pntd.0000885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha. Nat Chem Biol. 2010;6(11):829–36. https://doi.org/10.1038/nchembio.453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M, et al. Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science. 2003;299(5615):2039–45. https://doi.org/10.1126/science.1081403.

    Article  CAS  PubMed  Google Scholar 

  109. Li B, Fei DL, Flaveny CA, Dahmane N, Baubet V, Wang Z, et al. Pyrvinium attenuates Hedgehog signaling downstream of smoothened. Cancer Res. 2014;74(17):4811–21. https://doi.org/10.1158/0008-5472.CAN-14-0317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. De Witt M, Gamble A, Hanson D, Markowitz D, Powell C, Al Dimassi S, et al. Repurposing mebendazole as a replacement for vincristine for the treatment of brain tumors. Mol Med. 2017;23:50–6. https://doi.org/10.2119/molmed.2017.00011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bai RY, Staedtke V, Rudin CM, Bunz F, Riggins GJ. Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis. Neuro Oncol. 2015;17(4):545–54. https://doi.org/10.1093/neuonc/nou234.

    Article  CAS  PubMed  Google Scholar 

  112. Dakshanamurthy S, Issa NT, Assefnia S, Seshasayee A, Peters OJ, Madhavan S, et al. Predicting new indications for approved drugs using a proteochemometric method. J Med Chem. 2012;55(15):6832–48. https://doi.org/10.1021/jm300576q.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Larsen AR, Bai RY, Chung JH, Borodovsky A, Rudin CM, Riggins GJ, et al. Repurposing the antihelmintic mebendazole as a hedgehog inhibitor. Mol Cancer Ther. 2015;14(1):3–13. https://doi.org/10.1158/1535-7163.Mct-14-0755-t.

    Article  CAS  PubMed  Google Scholar 

  114. Bai RY, Staedtke V, Wanjiku T, Rudek MA, Joshi A, Gallia GL, et al. Brain penetration and efficacy of different mebendazole polymorphs in a mouse brain tumor model. Clin Cancer Res. 2015;21(15):3462–70. https://doi.org/10.1158/1078-0432.CCR-14-2681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Koto KS, Lescault P, Brard L, Kim K, Singh RK, Bond J, et al. Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma. Int J Oncol. 2011;38(5):1329–41. https://doi.org/10.3892/ijo.2011.971.

    Article  CAS  PubMed  Google Scholar 

  116. Söderlund J, Erhardt S, Kast RE. Acyclovir inhibition of IDO to decrease Tregs as a glioblastoma treatment adjunct. J Neuroinflammation. 2010;7:44. https://doi.org/10.1186/1742-2094-7-44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang B, Wang X, Cai F, Chen W, Loesch U, Bitzer J, et al. Effects of salinomycin on human ovarian cancer cell line OV2008 are associated with modulating p38 MAPK. Tumour Biol. 2012;33(6):1855–62. https://doi.org/10.1007/s13277-012-0445-9.

    Article  CAS  PubMed  Google Scholar 

  118. Ketola K, Hilvo M, Hyotylainen T, Vuoristo A, Ruskeepaa AL, Oresic M, et al. Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br J Cancer. 2012;106(1):99–106. https://doi.org/10.1038/bjc.2011.530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A. 2011;108(32):13253–7. https://doi.org/10.1073/pnas.1110431108.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Zhou S, Wang F, Zhang Y, Johnson MR, Qian S, Wu M, et al. Salinomycin suppresses PDGFRbeta, MYC, and Notch signaling in human medulloblastoma. Austin J Pharmacol Ther. 2014;2(3):1020.

    PubMed  Google Scholar 

  121. Natarajan S, Li Y, Miller EE, Shih DJ, Taylor MD, Stearns TM, et al. Notch1-induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma. Cancer Res. 2013;73(17):5381–90. https://doi.org/10.1158/0008-5472.CAN-13-0033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Pace JR, Jog R, Burgess DJ, Hadden MK. Formulation and evaluation of itraconazole liposomes for hedgehog pathway inhibition. J Liposome Res. 2019:1–7. https://doi.org/10.1080/08982104.2019.1668011.

  123. Shaimerdenova M, Karapina O, Mektepbayeva D, Alibek K, Akilbekova D. The effects of antiviral treatment on breast cancer cell line. Infect Agent Cancer. 2017;12:18. https://doi.org/10.1186/s13027-017-0128-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Baryawno N, Rahbar A, Wolmer-Solberg N, Taher C, Odeberg J, Darabi A, et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest. 2011;121(10):4043–55. https://doi.org/10.1172/JCI57147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wang LH, Chittick GE, McDowell JA. Single-dose pharmacokinetics and safety of abacavir (1592U89), zidovudine, and lamivudine administered alone and in combination in adults with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1999;43(7):1708–15.

    Article  CAS  Google Scholar 

  126. Yegorov YE, Chernov DN, Akimov SS, Bolsheva NL, Krayevsky AA, Zelenin AV. Reverse transcriptase inhibitors suppress telomerase function and induce senescence-like processes in cultured mouse fibroblasts. FEBS Lett. 1996;389(2):115–8. https://doi.org/10.1016/0014-5793(96)00533-9.

    Article  CAS  PubMed  Google Scholar 

  127. Rossi A, Russo G, Puca A, La Montagna R, Caputo M, Mattioli E, et al. The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells. Int J Cancer. 2009;125(1):235–43. https://doi.org/10.1002/ijc.24331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Amano H, Hayashi I, Endo H, Kitasato H, Yamashina S, Maruyama T, et al. Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth. J Exp Med. 2003;197(2):221–32. https://doi.org/10.1084/jem.20021408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Leidgens V, Seliger C, Jachnik B, Welz T, Leukel P, Vollmann-Zwerenz A, et al. Ibuprofen and diclofenac restrict migration and proliferation of human glioma cells by distinct molecular mechanisms. PLoS One. 2015;10(10):e0140613. https://doi.org/10.1371/journal.pone.0140613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shi J, Leng W, Zhao L, Xu C, Wang J, Chen X, Wang Y, Peng X (2017) Nonsteroidal anti-inflammatory drugs using and risk of head and neck cancer: a dose-response meta analysis of prospective cohort studies. Oncotarget 8 (58):99066-99074. doi:10.18632/oncotarget.21524

  131. Harris RE, Chlebowski RT, Jackson RD, Frid DJ, Ascenseo JL, Anderson G, et al. Breast cancer and nonsteroidal anti-inflammatory drugs: prospective results from the Women’s Health Initiative. Cancer Res. 2003;63(18):6096–101.

    CAS  PubMed  Google Scholar 

  132. Trabert B, Ness RB, Lo-Ciganic WH, Murphy MA, Goode EL, Poole EM, Brinton LA, Webb PM, Nagle CM, Jordan SJ, Risch HA, Rossing MA, Doherty JA, Goodman MT, Lurie G, Kjær SK, Hogdall E, Jensen A, Cramer DW, Terry KL, Vitonis A, Bandera EV, Olson S, King MG, Chandran U, Anton-Culver H, Ziogas A, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Wu AH, Pearce CL, Pike MC, Berchuck A, Schildkraut JM, Wentzensen N (2014) Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium. J Natl Cancer Inst 106 (2):djt431. doi:https://doi.org/10.1093/jnci/djt431

  133. Vidal AC, Howard LE, Moreira DM, Castro-Santamaria R, Andriole GL, Freedland SJ. Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study. Clin Cancer Res. 2015;21(4):756–62. https://doi.org/10.1158/1078-0432.CCR-14-2235.

    Article  CAS  PubMed  Google Scholar 

  134. Friis S, Riis AH, Erichsen R, Baron JA, Sørensen HT. Low-dose aspirin or nonsteroidal anti-inflammatory drug use and colorectal cancer risk: a population-based, case-control study. Ann Intern Med. 2015;163(5):347–55. https://doi.org/10.7326/m15-0039.

    Article  PubMed  Google Scholar 

  135. Verschuur A, Heng-Maillard MA, Dory-Lautrec P, Truillet R, Jouve E, Chastagner P, et al. Metronomic four-drug regimen has anti-tumor activity in pediatric low-grade glioma; the results of a phase II clinical trial. Front Pharmacol. 2018;9:00950. https://doi.org/10.3389/fphar.2018.00950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yang MY, Lee HT, Chen CM, Shen CC, Ma HI. Celecoxib suppresses the phosphorylation of STAT3 protein and can enhance the radiosensitivity of medulloblastoma-derived cancer stem-like cells. Int J Mol Sci. 2014;15(6):11013–29. https://doi.org/10.3390/ijms150611013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chen KH, Hsu CC, Song WS, Huang CS, Tsai CC, Kuo CD, et al. Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells. Childs Nerv Syst. 2010;26(11):1605–12. https://doi.org/10.1007/s00381-010-1190-2.

    Article  PubMed  Google Scholar 

  138. Baryawno N, Sveinbjornsson B, Eksborg S, Orrego A, Segerstrom L, Oqvist CO, et al. Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets. Neuro Oncol. 2008;10(5):661–74. https://doi.org/10.1215/15228517-2008-035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Eslin D, Lee C, Sankpal UT, Maliakal P, Sutphin RM, Abraham L, et al. Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study. Tumour Biol. 2013;34(5):2781–9. https://doi.org/10.1007/s13277-013-0836-6.

    Article  CAS  PubMed  Google Scholar 

  140. Abdelrahim M, Baker CH, Abbruzzese JL, Safe S. Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst. 2006;98(12):855–68. https://doi.org/10.1093/jnci/djj232.

    Article  CAS  PubMed  Google Scholar 

  141. Shelake S, Sankpal UT, Paul Bowman W, Wise M, Ray A, Basha R. Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth. Invest New Drugs. 2017;35(2):158–65. https://doi.org/10.1007/s10637-016-0417-9.

    Article  CAS  PubMed  Google Scholar 

  142. King JG Jr, Khalili K. Inhibition of human brain tumor cell growth by the anti-inflammatory drug, flurbiprofen. Oncogene. 2001;20(47):6864–70. https://doi.org/10.1038/sj.onc.1204907.

    Article  CAS  PubMed  Google Scholar 

  143. Ng CG, Boks MP, Smeets HM, Zainal NZ, de Wit NJ. Prescription patterns for psychotropic drugs in cancer patients; a large population study in the Netherlands. Psychooncology. 2013;22(4):762–7. https://doi.org/10.1002/pon.3056.

    Article  PubMed  Google Scholar 

  144. Mortensen PB. The incidence of cancer in schizophrenic patients. J Epidemiol Community Health. 1989;43(1):43–7. https://doi.org/10.1136/jech.43.1.43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen JJ, Cai N, Chen GZ, Jia CC, Qiu DB, Du C, Liu W, Yang Y, Long ZJ, Zhang Q (2017) The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma. Oncotarget 8 (11):17593-17609. doi:10.18632/oncotarget.4307

  146. Ludwig J, Weseloh R, Karschin C, Liu Q, Netzer R, Engeland B, et al. Cloning and functional expression of rat eag2, a new member of the ether-à-go-go family of potassium channels and comparison of its distribution with that of eag1. Mol Cell Neurosci. 2000;16(1):59–70. https://doi.org/10.1006/mcne.2000.0851.

    Article  CAS  PubMed  Google Scholar 

  147. Huang X, Dubuc AM, Hashizume R, Berg J, He Y, Wang J, et al. Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics. Genes & development. 2012;26(16):1780–96. https://doi.org/10.1101/gad.193789.112.

    Article  CAS  Google Scholar 

  148. Huang X, He Y, Dubuc AM, Hashizume R, Zhang W, Reimand J, et al. EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat Neurosci. 2015;18(9):1236–46. https://doi.org/10.1038/nn.4088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mascaro-Cordeiro B, Oliveira ID, Tesser-Gamba F, Pavon LF, Saba-Silva N, Cavalheiro S, et al. Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma. Childs Nerv Syst. 2018;34(8):1497–509. https://doi.org/10.1007/s00381-018-3817-7.

    Article  PubMed  Google Scholar 

  150. Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC. Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther. 2005;4(12):1912–22. https://doi.org/10.1158/1535-7163.MCT-05-0184.

    Article  CAS  PubMed  Google Scholar 

  151. Sassi RB, Nicoletti M, Brambilla P, Mallinger AG, Frank E, Kupfer DJ, et al. Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett. 2002;329(2):243–5. https://doi.org/10.1016/s0304-3940(02)00615-8.

    Article  CAS  PubMed  Google Scholar 

  152. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, et al. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry. 2000;48(1):1–8. https://doi.org/10.1016/s0006-3223(00)00252-3.

    Article  CAS  PubMed  Google Scholar 

  153. Mao CD, Hoang P, DiCorleto PE. Lithium inhibits cell cycle progression and induces stabilization of p53 in bovine aortic endothelial cells. J Biol Chem. 2001;276(28):26180–8. https://doi.org/10.1074/jbc.M101188200.

    Article  CAS  PubMed  Google Scholar 

  154. Ronchi A, Salaroli R, Rivetti S, Della Bella E, Di Tomaso T, Voltattorni M, et al. Lithium induces mortality in medulloblastoma cell lines. Int J Oncol. 2010;37(3):745–52. https://doi.org/10.3892/ijo_00000724.

    Article  CAS  PubMed  Google Scholar 

  155. Zhukova N, Ramaswamy V, Remke M, Martin DC, Castelo-Branco P, Zhang CH, et al. WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. Acta Neuropathol Commun. 2014;2:174. https://doi.org/10.1186/s40478-014-0174-y.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Kurita JI, Hirao Y, Nakano H, Fukunishi Y, Nishimura Y. Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities. Sci Rep. 2018;8(1):13763. https://doi.org/10.1038/s41598-018-31852-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Spiller SE, Ditzler SH, Pullar BJ, Olson JM. Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J Neurooncol. 2008;87(2):133–41. https://doi.org/10.1007/s11060-007-9505-1.

    Article  CAS  PubMed  Google Scholar 

  158. Hallahan AR, Pritchard JI, Chandraratna RA, Ellenbogen RG, Geyer JR, Overland RP, et al. BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med. 2003;9(8):1033–8. https://doi.org/10.1038/nm904.

    Article  CAS  PubMed  Google Scholar 

  159. Gumireddy K, Sutton LN, Phillips PC, Reddy CD. All-trans-retinoic acid-induced apoptosis in human medulloblastoma: activation of caspase-3/poly(ADP-ribose) polymerase 1 pathway. Clin Cancer Res. 2003;9(11):4052–9.

    CAS  PubMed  Google Scholar 

  160. Mancini D, Pinney S, Burkhoff D, LaManca J, Itescu S, Burke E, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation. 2003;108(1):48–53. https://doi.org/10.1161/01.Cir.0000070421.38604.2b.

    Article  CAS  PubMed  Google Scholar 

  161. Bahmad HF, Mouhieddine TH, Chalhoub RM, Assi S, Araji T, Chamaa F, Itani MM, Nokkari A, Kobeissy F, Daoud G, Abou-Kheir W (2018) The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma. Oncotarget 9 (71):33549-33561. doi:10.18632/oncotarget.26088

  162. Mohan AL, Friedman MD, Ormond DR, Tobias M, Murali R, Jhanwar-Uniyal M. PI3K/mTOR signaling pathways in medulloblastoma. Anticancer Res. 2012;32(8):3141–6.

    CAS  PubMed  Google Scholar 

  163. Garner EF, Williams AP, Stafman LL, Aye JM, Mroczek-Musulman E, Moore BP, et al. FTY720 decreases tumorigenesis in group 3 medulloblastoma patient-derived xenografts. Sci Rep. 2018;8(1):6913. https://doi.org/10.1038/s41598-018-25263-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mancuso M, Leonardi S, Ceccarelli M, Pasquali E, De Stefano I, Prisco MG, et al. Protective role of 17 β-estradiol on medulloblastoma development in Patched 1 heterozygous mice. Int J Cancer. 2010;127(12):2749–57. https://doi.org/10.1002/ijc.25293.

    Article  CAS  PubMed  Google Scholar 

  165. Belcher SM, Ma X, Le HH. Blockade of estrogen receptor signaling inhibits growth and migration of medulloblastoma. Endocrinology. 2009;150(3):1112–21. https://doi.org/10.1210/en.2008-1363.

    Article  CAS  PubMed  Google Scholar 

  166. Ciucci A, Meco D, De Stefano I, Travaglia D, Zannoni GF, Scambia G, et al. Gender effect in experimental models of human medulloblastoma: does the estrogen receptor β signaling play a role? PloS one. 2014;9(7):e101623. https://doi.org/10.1371/journal.pone.0101623.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Spiller SE, Logsdon NJ, Deckard LA, Sontheimer H. Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo. BMC Cancer. 2011;11:136. https://doi.org/10.1186/1471-2407-11-136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Di Magno L, Manni S, Di Pastena F, Coni S, Macone A, Cairoli S, Sambucci M, Infante P, Moretti M, Petroni M, Nicoletti C, Capalbo C, De Smaele E, Di Marcotullio L, Giannini G, Battistini L, Goffredo BM, Iorio E, Agostinelli E, Maroder M, Canettieri G (2020) Phenformin inhibits hedgehog-dependent tumor growth through a complex I-independent redox/corepressor module. Cell Rep 30 (6):1735-1752.e1737. doi:https://doi.org/10.1016/j.celrep.2020.01.024

  169. Mouhieddine TH, Nokkari A, Itani MM, Chamaa F, Bahmad H, Monzer A, et al. Metformin and Ara-a effectively suppress brain cancer by targeting cancer stem/progenitor cells. Frontiers in neuroscience. 2015;9:442. https://doi.org/10.3389/fnins.2015.00442.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014;9(2):e87366. https://doi.org/10.1371/journal.pone.0087366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zha J, Chen F, Dong H, Shi P, Yao Y, Zhang Y, et al. Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition. J Transl Med. 2014;12:163. https://doi.org/10.1186/1479-5876-12-163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, et al. Disulfiram modulated ROS–MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. British Journal of Cancer. 2011;104(10):1564–74. https://doi.org/10.1038/bjc.2011.126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Chen D, Cui QC, Yang H, Dou QP. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006;66(21):10425–33. https://doi.org/10.1158/0008-5472.CAN-06-2126.

    Article  CAS  PubMed  Google Scholar 

  174. Madala HR, Punganuru SR, Ali-Osman F, Zhang R, Srivenugopal KS (2017) Brain- and brain tumor-penetrating disulfiram nanoparticles: sequence of cytotoxic events and efficacy in human glioma cell lines and intracranial xenografts. Oncotarget 9 (3):3459-3482. doi:10.18632/oncotarget.23320

  175. Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduction and Targeted Therapy. 2020;5(1):113. https://doi.org/10.1038/s41392-020-00213-8.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to thank all members of the Neuroscience Research Center, Faculty of Medicine, Lebanese University (Beirut, Lebanon), and the Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center (Miami Beach, FL, USA), for their help on this work. This work was not funded.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author information

Author notes

  1. Hussein Hammoud and Zahraa Saker are authors who contributed equally to this work as co-first authors.

    Hisham F. Bahmad and Sanaa Nabha are authors who contributed equally to this work as co-senior authors.

Authors and Affiliations

  1. Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Hadas, Beirut, Lebanon

    Hussein Hammoud MSc, Zahraa Saker MSc, Hayat Harati PhD, Youssef Fares MD, PhD & Sanaa Nabha PhD

  2. Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon

    Youssef Fares MD, PhD

  3. Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL, 33140, USA

    Hisham F. Bahmad MD, MSc

  4. Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

    Hisham F. Bahmad MD, MSc

Authors
  1. Hussein Hammoud MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zahraa Saker MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hayat Harati PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Youssef Fares MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hisham F. Bahmad MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sanaa Nabha PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.F. Bahmad and S. Nabha conceived the concept and idea of the present review. H.F. Bahmad and S. Nabha worked on the study design strategy and selected the topics to be discussed. H. Hammoud, Z. Saker, H.F. Bahmad, and S. Nabha did literature searches and screened titles and abstracts for relevance. H. Hammoud and Z. Saker abstracted the data from the eligible full text articles, analyzed and interpreted the data, and drafted the manuscript. H. Harati and Y. Fares revised the final draft of the manuscript. H.F. Bahmad and S. Nabha critically revised the manuscript with input from the entire team. All authors have read and approved the final draft.

Corresponding authors

Correspondence to Hisham F. Bahmad MD, MSc or Sanaa Nabha PhD.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Neuro-oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hammoud, H., Saker, Z., Harati, H. et al. Drug Repurposing in Medulloblastoma: Challenges and Recommendations. Curr. Treat. Options in Oncol. 22, 6 (2021). https://doi.org/10.1007/s11864-020-00805-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11864-020-00805-0

Keywords

Search

Navigation