Oncological Management of Medulloblastoma and New Viral Therapeutic Targets
Authors: A. Taqaddas
Medulloblastoma (MB) is one of the most prevalent brain tumours among paediatrics. Although its management has evolved over time still there is need to find new therapeutic targets for MB that can result in less normal tissue toxicity while improving survival and reducing recurrence. This literature review is aimed at finding new potential therapeutic targets for MB focusing on viruses that can be used as potential targets for MB. The review also gives an over-view of management of paediatric Medulloblastoma focusing on Radiotherapy management.
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 K. Chao, C. Perez, and L. Brady, eds. Radiation Oncology Management Decisions. Philadelphia: Lippincott Williams & Wilkins, 2002.
 A. Brandes, and M. Paris, “Review of the prognostic factors in medulloblastoma of children and adults,” Critical Reviews in Oncology / Hematology, 50, 121-128, 2004
 A. Paulino, “Current multimodality management of medulloblastoma,” Current problems in Cancer, 26, 317-356. 2002.
 P. Plowman, and A. Pearson, “Tumours of the central nervous system,” in Paediatric Oncology. Clinical Practice and Controversies, 2nd ed. C. Pinkerton, and P. Plowman P, eds. London: Chapman & Hall, 1997.
 R. Packer, “Childhood medlloblastoma: progress and future challenges,” Brain and Development, 21, 75-81, 1999.
 Bomford, and I. Kunkler, Walter and Miller’ Textbook of Radiotherapy: radiation physics, therapy and oncology. 3rd ed. Edinburgh: Churchill Livingstone, 2003.
 Louis, H. Ohgaki, O. Wiestler, et al., eds. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: IARC Press, 2007.
 M. Taylor, P. Northcott, A. Korshunov, M. Remke, Y. Chao, S. Clifford et al., “Molecular subgroups of medulloblastoma: the current consensus,” Aceta Neuropathologica, 123, 465-472, 2012.
 M. Kool, A. Korshunov, M. Remke, D. Jones, M. Schlanstein, P. Northcott, et al., “Molecular subgroups of medulloblastoma: An international meta-analysis of transcriptome, genetic aberrations, and clinical data of wnt, shh, group 3, and group 4 medulloblastomas,” Acta Neuropathologica, 123, 473-84, 2012.
 R. Potter, T. Czech, I. Slavc, Wimberger-Prayer, and H. Budka, “Tumours of the central nervous system,” in Cancer in children, P. Voute, C. Kalifa C, and A. Barrett, eds. Oxford: Oxford University Press, 1998.
 M. Fouladi, A. Gajjar, J. Boyett, A. Walter, S. Thompson, T. Merchant, et al., "Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric meduloblastoma or primitive neuroectodermal tumor," Journal Clinical Oncology, 17, 3234-3237, 1999.
 R. Taylor, “United Kingdom Children’s Cancer Study Group (UKCCSG) Radiotherapy and Brain Tumour Groups: Medulloblastoma/PNET and Craniospinal Radiotherapy (CSRT): Report of a Workshop held in Leeds,” Clinical Oncology, 13, 58-64, 1999.
 J. Phi, J. Lee, K. Wang, B. Cho, I. Kim, and C. Park, “Cerebrospinal fluid M staging for medulloblastoma: Reappraisal of Chang's M staging based on the CSF flow,” Neuro-Oncology, 13, 334-344, 2011.
 Michiels, J. Heikens, M. Jansen, F. Oldenburger, & T. Voute, “Are clinical parameters valuable prognostic factors in childhood primitive neuroectodermal tumours? A multivariate analysis of 105 cases,” Radiotherapy & Oncology, 54, 229-238, 2000.
 Jenkin, M. Al Shabanah, E. Al Shail, A. Gray, M. Hssounah, Y. Khafaga, et al., “Prognostic factors for medulloblastoma,” International Journal of Radiation Oncology, Biology, Physics, 47, 573-584, 2000.
 S. Rieken, A.. Moher, D. Hebermehl, T. Welzel, K. Lindel, O. Witt, et al., “Outcome and Prognostic factors of radiation therapy for medulloblastoma,” International Journal of Radiation Oncology, Biology, Physics, 81, e7-e13, 2011.
 O. Araujo, K. de Trindade, N. Trompieri, J. Fontenele, and F. Felix, “Analysis of survival and prognostic factors of pediatric patients with brain tumor,” Journal of Pediatric (Rio J), 87, 425–32, 2011
 M. Massimino, M. Antonelli, L. Gandola, R. Miceli, B. Pollo, V. Biassoni, et al., “Histological variants of medulloblastoma are the most powerful clinical prognostic indicators,” Pediatric Blood Cancer, 60, 210-6, 2013.
 Z. Shinwari, H. Al-Hindi, E. Al-Shail, Y. Khafaga, A. Al-Kofide, N. Al- Kum, et al., “Response of Medulloblastoma Cells to Vincristine and Lomustine: Role of TRKC, CTNNB1, and STK15,” Anticancer Research, 31, 1721-1734, 2011.
 A. Ellison, O. Onilude, J. Lindsey, M. Lusher, C. Weston, and R. Taylor, “β-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumour Committee,” Journal of Clinical Oncology, 23, 7951- 7957, 2005.
 K. Neben, A. Korshunov, A. Benner, G. Wrobel, M. Hahn, and F. Kokocinski, “Microarray based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival,” Cancer Research, 64, 3103-3111, 2004.
 Z. Zhang, J. Xu, Y. Ren, Y. Yao, K. Li, H. Ng, et al., “Medulloblastoma in China: Clinicopathologic Analyses of SHH, WNT, and non- SHH/WNTMolecular subgroups Reveal Different Therapeutic Responses to Adjuvant Chemotherapy,” PLoS ONE, 9, e99490. Available online: http://www.brainlife.org/fulltext/2014/ Zhang_ZY140616.pdf. (Accessed 06/01/2015).
 Albright, L. Wisoff, P. Zeltzer, J. Boyett, L. Rorke, and P. Stanley, “Effects of medulloblastoma resections on outcome in children: a report from the children’s cancer group,” Neurosurgery, 38, 265-271, 1996.
 Y. Khafaga, A. Kandil, A. Jamshed, M. Hassounah, E. DeVol, and A. Gray A., “Treatment results for 149 medulloblastoma patients from one institution,” International Journal of Radiation Oncology, Biology, Physics, 35, 501-506, 1996.
 R. Taylor, C. Bailey, K. Robinson, C. Weston, D. Ellison, J. Ironside, et al., “Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0- M1 medulloblastoma,” International Journal of Radiation Oncology, Biology, Physics, 58, 1184-1193, 2004
 L. Sun, S. Yeh, C. Wang, E. Huang, H. Chen, and H. Hsu, “Postoperative radiation therapy for medulloblastoma – high recurrence rate in the subfrontal region,” Journal of Neuro-Oncology, 58, 77-85, 2002.
 R. Taylor, C. Bailey, K. Robinson, C. Weston, D. Ellison, J. Ironside, et al., “Results of a Randomized Study of Preradiation Chemotherapy Versus Radiotherapy Alone for Nonmetastatic Medulloblastoma: The International Society of Paediatric Oncology / United Kingdom Children’s Cancer Study Group PNET-3 Study,” Journal of Clinical Oncology, 21, 1581-1591, 2003.
 J. Douglas, J. Barker, R. Ellenbogen, and J. Geyer, “Concurrent chemotherapy and reduced dose cranial spinal irradiation followed by conformal posterior fossa tumour bed boost for average-risk medulloblastoma: efficacy and patterns of failure,” International Journal of Radiation Oncology Biology, Physics, 58, 1161-1164, 2004.
 R. Packer, J. Golwein, H. Nicholson, L. Vezina, J. Allen and M. Ris et al., “Treatment of children with medulloblastoma with reduced craniospinal radiation therapy and adjuvant chemotherapy: a children’s cancer group study,” Journal of Clinical Oncology, 17, 2127–2136, 1999.
 P. Thomas, M. Deutsch, J. Kepner, J. Boyett, J. Krischer, P. Aronin, et al., “Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis Irradiation,” Journal of Clinical Oncology, 18, 3004-11, 2000.
 R. Jakacki, H. Feldman, C. Jamison, J. Boaz, T. Luerssen, and R. Timmerman, “A pilot study of preirradiation chemotherapy and 1800 cGy craniospinal irradiation in young children with medulloblastoma,” International Journal of Radiation Oncology, Bioliogy, Physics, 60, 531-536, 2004.
 A. Freeman, R. Taylor, R. Kortmann, and C. Carrie, “Radiotherapy for medulloblastoma in children: a perspective on current international clinical research effort,” Medical and Pediatric Oncology, 39, 99–108, 2002.
 A. Bouffet, J. Gentet, F. Doz, P. Tron, H. Roche, and D. Plantaz et al., “Metastatic Medulloblastoma: the experience of the French Cooperative M7 Group,” European Journal of Cancer, 30, 1478-1483. 1994.
 K. Mah, C. Danjoux, S. Manship, N. Makhani, M. Cardoso, and K. Sixel, “Computed tomographic simulation of craniospinal fields in pediatric patients: improved treatment accuracy and patient comfort,” International Journal of Radiation Oncology, Biology, Physics, 41, 997- 1003, 1998.
 A. Chang, P. Wong, K. Forser, M. Petru, A. Kowalski, and M. Maor M., “Verification Techniques and Dose Distribution for Computed Tomographic Planned Supine Craniospinal Radiation Therapy,” Medical Dosimetry, 28, 127-131, 2003.
 R. Miralbell, A. Bleher, P. Huguenin, G. Ries, R. Kann, R. Mirimanoff, et al., “Paediatric medulloblastoma: Radiation treatment technique and pattern of failure,” International Journal of Radiation oncology, Biology, Physics, 37, 523-529, 1997.
 J. Dobbs, A. Barrett, and D. Ash, Practical Radiotherapy Planning. 3rd ed. London: Edward Arnold, 1999.
 A. Narayana, S. Jeswani, and A. Paulino, “The Cranial-spinal Junction in Medulloblastoma: Does it Matter?,”’ International Journal of Radiation Oncology, Biology, Physics, 44, 81-84, 1999.
 A. Scharf, A. Paulino, and K. Golberg, “Determination of the inferior border of the thecal sac using magnetic resonance imaging: implications on radiation therapy treatment planning,” International Journal of Radiation Oncology, Biology, Physics, 41, 621-624, 1998.
 A. Paulino, A. Narayana, M. Mohideen, and S. Jeswani S., “Posterior fossa boost in medulloblastoma: an analysis of dose to surrounding structures using 3-dimensional (conformal) radiotherapy,” International Journal of Radiation Oncology, Biology, Physics, 46, 281-286, 2000.
 A. Paulino, B. Wen, N. Mayr, R. Tannous, T. Loew, F. Goldman, et al., “Protracted Radiotherapy Treatment Duration in Medulloblastoma,” American Journal of Clinical Oncology, 26, 55-59, 2003.
 W. Hartsell, A. Guijar, R. Heidemann, J. Langston, R. Sanford, A. Walter, et al., “Patterns of failure in children with medulloblastoma: Effects of preirradiation chemotherapy,” International Journal of Radiation Oncology, Biology, Physics, 39, 15-24, 1997.
 J. Kortann, J. Kuhl, B. Timmerman, U. Mittler, C. Urban, V. Budach, et al., “Postoperative chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT 91,” International Journal of Radiation Oncology, Biology, Physics, 46, 269-279, 2000.
 A. Paulino, A. Mazloom, B. Teh, M. South, M. Okcu, J. Su et al., “ Local Control after Craniospinal Irradiation, Intensity Modulated Radiotherapy Boost, and Chemotherapy in Childhood Medulloblastoma,” Cancer, 117, 635-641, 2011.
 A. Paulino, M. Lobo, B. Teh, M. Okcu, M. South, E. Butler et al., “Ototoxicity after inten- sity-modulated radiation therapy and cisplatinbased chemo-therapy in children with medulloblastoma,” International Journal of Radiation Oncology, Biology, Physics, 78, 1445-50, 2010.
 E. Huang, B. Teh, D. Strother, Q. Davis, J. Chiu, H. Lu, et al., “Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity,” International Journal of Radiation Oncology, Biology, Physics, 52, 599-605, 2002.
 P. Myers, P. Mavroidis, N. Papanikolaou, and S. Stathakis, “Comparing Conformal arc radiotherapy and helical tomotherapy in craniospinal irradiation planning,” Journal of Applied Clinical Medical Physics, 15, 12-28, 2014.
 Graham, and T. Cloughesy, “Brain tumour treatment: Chemotherapy and other new developments,” Seminars in Oncology Nursing, 20, 260-272, 2004.
 M. Hopkins, J. Pownall, and L. Scott L. “Acute and sub acute side effects of radiotherapy,” in Paediatric Oncology: Acute Nursing Care, F. Gibson, and M. Evans, eds. London: Whurr Publishers Ltd, 2000.
 S. Harden, N. Twyman, D. Lomas, D. Williams, N. Burnet, and M. Williams, “A method for reducing ovarian doses in whole neuro-axis irradiation for medulloblastoma,” Radiotherapy and Oncology, 69, 183- 188, 2003.
 S. Muirhead, E. Hsu, L. Grimard, and D. Keene, “Endocrine cmplications of Pediatric brain tumours: case series and literature review,” Paediatric Neurology, 27, 165-170, 2002.
 L. Scott, J. Pownall, and M. Hopkins, “Late effects of radiotherapy,” in Paediatric Oncology: Acute Nursing Care, F. Gibson, and M. Evans, eds. London: Whurr Publishers Ltd, 2000.
 J. Grill, V. Renaux, C. Bulteau, D. Viguier, C. Levy-Piebois, C. Sainte- Rose, et al., “Long-term intellectual outcome in children with posterior fossa tumours according to radiation doses and volumes,” International Journal of Radiation Oncology, Biology, Physics, 45, 37-145, 1999.
 Reeves, S. Palmer, W. Reddick, T. Merchant, G. Buchanan, and A. Gajjar, “Attention and memory functioning among paediatric patients with medulloblastoma,” Journal of Pediatric Psychology, 31, 272-80, 2006.
 K. Nishiyama, S. Funakoshi, S. Izumuto, T. Ikeda, and Y. Oku, “Longterm effects of radiation for medulloblastoma on intellectual and physical development. A case report of monozygotic twins,” Cancer, 73, 2450-2455, 1994.
 S. Oberfield, D. Chin, N. Uli, R. David, C. Sklar, “Endocrine late effects of childhood Cancers,” The Journal of Pediatrics, 131, S37-S41, 1997.
 R. Mulhern, T. Merchant, A. Gajjar, W. Reddick, and L. Kun L., “Late neurocognitive sequelae in survivors of brain tumours in childhood,” The Lancet Oncology, 5, 399-408, 2004.
 R. Packer, A. Gajjar, G. Vezina, L. Rorke-Adams, P. Burger, P. Robertson, et al., “Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma,” Journal of clinical Oncology,24, 4202–4208, 2006.
 J. Heikens, E. Michiels, H. Behrendt, E. Endert, P. Bakker, and E. Fliers, “Long-term neuro-endocrine sequelae after treatment for childhood medulloblastoma,” European Journal of Cancer, 34, 1592–1597, 1998.
 T. Merchant, E. Kiehna, C. Li, H. Shukla, S. Sengupta, X. Xiong, et al., “Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma,” International Journal of Radiation Oncology, Biology, Physics, 65, 210–221, 2006.
 N. Baryawno, A. Rahbar, N. Wolmer-Solberg, C. Taher, J. Odeberg, A. Darabi et al., “Detection of Human Cytomegalovirus in medulloblastoma reveals a potential therapeutic target,” Journal of Clinical Investigation, 121, 4043-4055, 2011.
 J. Odeberg, N. Wolmer, S. Falci, M. Westgren, A. Seiger, C. Soderberg- Naucler, “Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells,” Journal of Virology, 80, 8929–8939, 2006. Available at: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1563895/pdf/0676-06.pdf. (Accessed 07/01/2015)
 J. Odeberg, N. Wolmer, S. Falci, M. Westgren, E. Sundtrom, A. Seiger, et al., “Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes,” Journal of Neuroscience Research, 85, 583–593, 2007
 P. Scotting, D. Walker, and G. Perilongo, “Childhood solid tumours: a developmental disorder,” Nature Reviews Cancer, 5, 481–488, 2005.
 Maussang, E. Langemeijer, C. Fitzsimon, M. Stigter-van, R. Dijkman, M. Borg et al., “The human cytomegalovirusencoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2,” Cancer Research, 69, 2861–2869, 2009.
 Wang, and R. Dubois, “Eicosanoids and cancer,” Nature Review Cancer, 10, 181–193, 2010.
 J. Mrena, J. Wiksten, A. Thiel, A. Kokkola, L. Pohjola, J. Lundin et al., “Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR,”. Clinical Cancer Research. 11, 7362–7368m 2005. Available at: http://clincancerres.aacrjournals.org/content/11/20/7362.full.pdf+html. (Accessed 05/01/2015).
 L. Soumaoro, H. Uetake, T. Higuchi, Y. Takagi, M. Enomoto, and K. Sugihara, “Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer,” Clinical Cancer Research, 10, 8465–8471, 2004.
 M. Michaelis and J. Cinatl, “The Story of Human Cytomegalovirus and Cancer; Increasing evidence and Open Questions,” Neoplasia, 11, 1-9, 2009.
 J. Cinatl, J. Cinatl, J. Vogel, H. Rabenau, B. Kornhuber, and H. Doerr “Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells,” Intervirology, 39, 259-269, 1996.
 J. Cinatl, J. Vogel, J. Cinatl, B. Weber, H. Rabenau, M. Novak, et al., “Long-term productive human cytomegalovirus infection of a human neuroblastoma cell line,” International Journal of Cancer, 65, 90–96, 1996.
 J. Cinatl, J. Cinatl, J. Vogel, R. Kotchetkov, P. Driever, H. Kabickova, et al., “Persistent human cyto-megalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells,” Cancer Research, 58 , 367–372, 1998.
 J. Cinatl, J. Vogel, R. Kotchetkov, and H. Wilhelm “Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression,” FEMS Microbiology Reviews, 28 ,59–77, 2004.
 Söderberg-Nauclér, “HCMV microinfections in inflammatory diseases and cancer,” Journal of Clinical Virology, 41, 218 – 223, 2008.
 Wang, and R. Dubois, “Prostaglandins and cancer,” Gut, 55, 115-22, 2006.
 Zhou, D. Li, M. Resnick, J. Wands, and W. Cao, “NADPH Oxidase NOX5-S and Nuclear factor kB1 Mediate Acid-induced microsomal Prostaglandin E Synthase-1 Expression in Barrett’s Esophageal Adenocarcinoma Cells,” Molecular Pharmacology, 83, 978-990, 2013.
 Tai, C. Ensor, M. Tong M, H. Zhou, F. Yan, “Prostaglandin catabolizing enzymes,” Prostaglandins & Other Lipid Mediators, 68–69, 483–493, 2002.
 Tai, M. Tong, and Y. Ding Y, “15-hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer,” Prostaglandins & Other Lipid Mediators, 83, 203-8, 2007.
 S. Myung, and I. Kim, “Role of prostaglandins in colon cancer,” The Korean Journal of Gastroenterology, 51, 274-9, 2008.
 S. Myung, R. Rerko, M. Yan, P. Platzer, K. Guda, A. Dotson, et al., “15- Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis,” Proceedings of the National Academy of Sciences of United States of America, 103, 12098-102.13, 2006.
 Pharm, M. Chen, A. Li, “Loss of 15-Hydroxyprostaglandin Dehydrogenase Increases Prostaglandin E2 in Pancreatic Tumours,” National Institute of Health, 39, 332-339, 2010.
 Galanis, “Therapeutic potential of oncolytic measles virus: promises and challenges,” Clinical Pharmacology and Therapeutics, 88, 620–625, 2010.
 A. Studebaker, C. Kreofsky, C. Pierson, S. Russell, E. Galanis, and C. Raffel C, “Treatment of medulloblastoma with a modified measles virus,” Neuro Oncology, 12, 1034–1042, 2010.
 A. Studebaker, B. Hutzen, C. Pierson, S. Russell, E. Galanis, C. Raffel, “Oncolytic measles virus prolongs survival in a murine model of cerebral spinal fluiddisseminated medulloblastoma,” Neuro Oncology, 14, 459–470, 2012.
 Hutzen, H. Bid, P. Houghton, C. Pierson, K. Powell, A. Bratasz, et al., “Treatment of medulloblastoma with oncolytic measles viruses expressioning the angiogenesis inhibitors endostatin and angiostatin,” BioMedical Central Cancer, 14, 2014.