The evolution of medulloblastoma therapy to personalized medicine

Recent advances in cancer genomics have revolutionized the characterization and classification of medulloblastomas. According to the current WHO guidelines, medulloblastomas are now classified into the following molecularly defined groups: Wnt signaling pathway (WNT)-activated, sonic hedgehog signaling pathway (SHH)-activated and tumor suppressor protein p53 (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH (i.e. group 3 and group 4). Importantly, genomic, epigenomic, and proteomic advances have created a potential paradigm shift in therapeutic options. The challenge now is to (i) translate these observations into new therapeutic approaches and (ii) employ these observations in clinical practice, utilizing the classification following a molecular analysis for diagnosis and application of new subgroup-specific targeted therapeutics.

[1]  David T. W. Jones,et al.  Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing , 2014, Nature.

[2]  D. Mitchell,et al.  Know your neighbors: Different tumor microenvironments have implications in immunotherapeutic targeting strategies across MB subgroups , 2016, Oncoimmunology.

[3]  Hans Clevers,et al.  Wnt/β-Catenin Signaling and Disease , 2012, Cell.

[4]  Words of wisdom. Re: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2014, European urology.

[5]  Roland Eils,et al.  Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. , 2014, Cancer cell.

[6]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[7]  Michael Kahn,et al.  Can we safely target the WNT pathway? , 2014, Nature Reviews Drug Discovery.

[8]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[9]  R. Moon,et al.  WNT signalling pathways as therapeutic targets in cancer , 2012, Nature Reviews Cancer.

[10]  Scott L. Pomeroy,et al.  Medulloblastomics: the end of the beginning , 2012, Nature Reviews Cancer.

[11]  Gary D. Bader,et al.  Divergent clonal selection dominates medulloblastoma at recurrence , 2016, Nature.

[12]  R. Packer,et al.  Management of and prognosis with medulloblastoma: therapy at a crossroads. , 2008, Archives of neurology.

[13]  R. Packer,et al.  SHH inhibitors for the treatment of medulloblastoma , 2015, Expert review of neurotherapeutics.

[14]  Could α5-GABA-A receptor activation be used as a target for managing medulloblastomas? , 2014, CNS oncology.

[15]  M. Roussel,et al.  Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. , 2016, Cancer cell.

[16]  J. Olson,et al.  DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences , 2009, Proceedings of the National Academy of Sciences.

[17]  Elaine R. Mardis,et al.  Novel mutations target distinct subgroups of medulloblastoma , 2012, Nature.

[18]  Michael C. Rusch,et al.  Cancer-associated DDX3X mutations drive stress granule assembly and impair global translation , 2016, Scientific Reports.

[19]  Arie Perry,et al.  Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy , 2016, Neuro-oncology.

[20]  Scott L. Pomeroy,et al.  Molecular subgroups of medulloblastoma: the current consensus , 2011, Acta Neuropathologica.

[21]  M. Kool,et al.  Risk stratification of childhood medulloblastoma in the molecular era: the current consensus , 2016, Acta Neuropathologica.

[22]  B. Schoch,et al.  Cerebellar mutism , 2004, Brain and Language.

[23]  Roland Eils,et al.  Active medulloblastoma enhancers reveal subgroup-specific cellular origins , 2016, Nature.

[24]  R. McLendon,et al.  Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations , 2015, Pediatric blood & cancer.

[25]  D. Ellison,et al.  Molecular pathology of paediatric central nervous system tumours , 2017, The Journal of pathology.

[26]  Scott L. Pomeroy,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 , 2012, Acta Neuropathologica.

[27]  Jessica M. Rusert,et al.  Proteomic profiling of high risk medulloblastoma reveals functional biology , 2015, Oncotarget.

[28]  Jill P. Mesirov,et al.  MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS , 2012, Nature.

[29]  Matthew J. Betts,et al.  Dissecting the genomic complexity underlying medulloblastoma , 2012, Nature.

[30]  Scott L. Pomeroy,et al.  TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma , 2013, Acta Neuropathologica.

[31]  Toshihiro Kumabe,et al.  Cytogenetic prognostication within medulloblastoma subgroups. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  David T. W. Jones,et al.  Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  T. Zhou,et al.  Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961. , 2013, Neuro-oncology.

[34]  T. Merchant,et al.  Children's Oncology Group's 2013 blueprint for research: Central nervous system tumors , 2013, Pediatric blood & cancer.

[35]  J. Mesirov,et al.  Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  Steven J. M. Jones,et al.  Subgroup-specific structural variation across 1,000 medulloblastoma genomes , 2012, Nature.

[37]  Michael C. Rusch,et al.  Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Yiai Tong,et al.  Subtypes of medulloblastoma have distinct developmental origins , 2010, Nature.

[39]  P. Bailey,et al.  MEDULLOBLASTOMA CEREBELLI: A COMMON TYPE OF MIDCEREBELLAR GLIOMA OF CHILDHOOD , 1925 .

[40]  J. Olson,et al.  HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. , 2016, Cancer cell.

[41]  David T. W. Jones,et al.  Transitioning from genotypes to epigenotypes: Why the time has come for medulloblastoma epigenomics , 2014, Neuroscience.

[42]  David T. W. Jones,et al.  Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. , 2013, The Lancet. Oncology.