The Everest Centre for Low-grade Paediatric Brain Tumours

Low-grade brain tumours make up the largest group of tumours of the central nervous system in children, accounting for about half of all brain tumors in under-18s. In Germany and the UK combined, more than 400 children and adolescents are diagnosed every year. These tumours are caused by changes in the DNA that lead to uncontrolled growth of cells in the brain or spinal cord. The term ‘low-grade’ indicates that the tumours are relatively slow-growing, and the risk of their spreading to other parts of the body is low. Given their location, however, these tumours can still be very difficult to treat, with children often suffering life-long health problems as a result of their disease and/or from side-effects of the treatment.

At the new Everest Centre for Low-Grade Paediatric Brain Tumours, launched in Summer 2017, research groups from Heidelberg (KiTZ and DKFZ), Berlin and London are aiming to dramatically improve our understanding of the biology of low-grade childhood brain tumours, with the long-term goal of being able to develop new treatment approaches. The Brain Tumour Charity, based in the UK, is supporting the project together with almost 6 million Euros (£5mio) of funding from supporters of the Everest in the Alps team.

The Everest Centre got its name from this extraordinary fundraising campaign, through which the family and friends of Toby (a low-grade glioma patient) want to raise awareness and promote research for this disease, based on the personal experiences of his exhausting journey. In 2015, 2018 and again in 2019, a group of ski-tourers traversed the alps over four days until they had covered an elevation gain equivalent to the height of Mt Everest (8,848m) – a grueling physical (and mental!) challenge. You can read more about their efforts here. So far, their efforts have raised over £4 million for The Brain Tumour Charity - THANK YOU!!

 

The Everest Principal Investigators:

David T.W. Jones (KiTZ & DKFZ Heidelberg)
Stefan M. Pfister (KiTZ, DKFZ & University Hospital Heidelberg)
Olaf Witt (KiTZ, DKFZ & University Hospital Heidelberg)
David Capper (DKTK & Charité Berlin)
Denise Sheer (Blizard Institute, Queen Mary’s, University of London)
Tom Jacques (University College London/Great Ormond Street Hospital Institute of Child Health)
J-P Martinez-Barbera (University College London/Great Ormond Street Hospital Institute of Child Health)
Darren Hargrave (University College London/Great Ormond Street Hospital Institute of Child Health)

 

How tumour cell hibernation may affect the growth of low-grade brain tumours

Some of our most exciting findings to date are related to a cellular process called ‘oncogene-induced senescence’ (OIS). This is a mechanism in which some cells enter a dormant or hibernation state when they sense incorrect activation of a tumour-driving pathway, as a natural protective mechanism. We have known for some time that low-grade brain tumour cells often enter this dormant state, but not what might be controlling it or how it relates to overall tumour growth. We have now been able to show that chemicals released by the hibernating tumour cells are able to promote this state in their neighbours, and suppress tumour growth. Interestingly, we also saw that patients with high levels of this hibernation program in their tumour were less likely to experience a tumour recurrence – something which we now want to further test as part of an upcoming European clinical trial being led by us (the LOGGIC study). Finally, we found that a particular type of new drugs might be able to specifically kill these hibernating cells, which likely make up a large fraction of the cells in a typical low-grade brain tumour. This is important, because these dormant cells are often resistant to currently used chemotherapies, which typically kill only actively growing cells. We are now in the early stages of discussing how this could potentially be tested in a new Everest clinical trial concept.

A full list of scientific publications from our team members that have been financially supported through funding of the Everest Centre can be found at the bottom of this page.

  1. Selt F, van Tilburg CM, Bison B, Sievers P, Harting I, Ecker J, Pajtler KW, Sahm F, Bahr A, Simon M, Jones DTW, Well L, Mautner VF, Capper D, Hernáiz Driever P, Gnekow A, Pfister SM, Witt O, Milde T. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol. 2020 Oct 7. doi: 10.1007/s11060-020-03640-3. Online ahead of print. PMID: 33026636

  2. Apps JR, Stache C, Gonzalez-Meljem JM, Gutteridge A, Chalker J, Jacques TS, Forshew T, Hölsken A, Martinez-Barbera JP. CTNNB1 mutations are clonal in adamantinomatous craniopharyngioma. Neuropathol Appl Neurobiol. 2020 Aug;46(5):510-514. doi: 10.1111/nan.12613. Epub 2020 Apr 2. PMID: 32125720

  3. Usta D, Sigaud R, Buhl JL, Selt F, Marquardt V, Pauck D, Jansen J, Pusch S, Ecker J, Hielscher T, Vollmer J, Sommerkamp AC, Rubner T, Hargrave D, van Tilburg CM, Pfister SM, Jones DTW, Remke M, Brummer T, Witt O, Milde T. A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF-Driven Pediatric Low-Grade Glioma Cells. Mol Cancer Ther. 2020 Aug;19(8):1736-1750. doi: 10.1158/1535-7163.MCT-19-1021. Epub 2020 May 25. PMID: 32451331

  4. Sommerkamp AC, Uhrig S, Stichel D, St-Onge P, Sun P, Jäger N, von Deimling A, Sahm F, Pfister SM, Korshunov A, Sinnett D, Jabado N, Wefers AK, Jones DTW. An optimized workflow to improve reliability of detection of KIAA1549:BRAF fusions from RNA sequencing data. Acta Neuropathol. 2020 May 31. doi: 10.1007/s00401-020-02167-1. [Epub ahead of print] PMID: 32476062

  5. Pickles JC, Stone TJ, Jacques TS. Methylation-based algorithms for diagnosis: experience from neuro-oncology. J Pathol. 2020 Apr;250(5):510-517. doi: 10.1002/path.5397. Epub 2020 Mar 10. PMID: 32057098

  6. Guerrero A, Guiho R, Herranz N, Uren A, Withers DJ, Martínez-Barbera JP, Tietze LF, Gil J. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell. 2020 Apr;19(4):e13133. doi: 10.1111/acel.13133. Epub 2020 Mar 16. PMID: 32175667

  7. Martinez-Barbera JP, Andoniadou CL. Biological Behaviour of Craniopharyngiomas. Neuroendocrinology. 2020;110(9-10):797-804. doi: 10.1159/000506904. Epub 2020 Mar 4. PMID: 32126562

  8. Perez E, Capper D. Invited Review: DNA methylation-based classification of paediatric brain tumours. Neuropathol Appl Neurobiol. 2020 Feb;46(1):28-47. doi: 10.1111/nan.12598. Epub 2020 Feb 19. PMID: 31955441

  9. Deng MY, Sill M, Sturm D, Stichel D, Witt H, Ecker J, Wittmann A, Schittenhelm J, Ebinger M, Schuhmann MU, Figarella-Branger D, Aronica E, Staszewski O, Preusser M, Haberler C, Lauten M, Schüller U, Hartmann C, Snuderl M, Dunham C, Jabado N, Wesseling P, Deckert M, Keyvani K, Gottardo N, Giangaspero F, von Hoff K, Ellison DW, Pietsch T, Herold Mende C, Milde T, Witt O, Kool M, Korshunov A, Wick W, von Deimling A, Pfister SM, Jones DTW, Sahm F. Diffuse Glioneuronal tumour with Oligodendroglioma-like features and Nuclear Clusters (DGONC) - a molecularly-defined glioneuronal CNS tumour class displaying recurrent monosomy 14. Neuropathol Appl Neurobiol. 2019 Dec 23. doi: 10.1111/nan.12590. [Epub ahead of print] PMID: 31867747
  10. Jones DTW, Bandopadhayay P, Jabado N. The Power of Human Cancer Genetics as Revealed by Low-Grade Gliomas. Annu Rev Genet. 2019 Dec 3;53:483-503. doi: 10.1146/annurev-genet-120417-031642. [Review] PMID: 31794268
  11. Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, Wolter K, Pombo J, Irvine EE, Innes AJ, Birch J, Glegola J, Manshaei S, Heide D, Dharmalingam G, Harbig J, Olona A, Behmoaras J, Dauch D, Uren AG, Zender L, Vernia S, Martínez-Barbera JP, Heikenwalder M, Withers DJ, Gil J. Cardiac glycosides are broad-spectrum senolytics. Nat Metab. 2019 Nov;1(11):1074-1088. doi: 10.1038/s42255-019-0122-z. Epub 2019 Oct 21. PMID: 31799499
  12. George SL, Izquierdo E, Campbell J, Koutroumanidou E, Proszek P, Jamal S, Hughes D, Yuan L, Marshall LV, Carceller F, Chisholm JC, Vaidya S, Mandeville H, Angelini P, Wasti A, Bexelius T, Thway K, Gatz SA, Clarke M, Al-Lazikani B, Barone G, Anderson J, Tweddle DA, Gonzalez D, Walker BA, Barton J, Depani S, Eze J, Ahmed SW, Moreno L, Pearson A, Shipley J, Jones C, Hargrave D, Jacques TS, Hubank M, Chesler L. A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations. Eur J Cancer. 2019 Nov;121:224-235. doi: 10.1016/j.ejca.2019.07.027. Epub 2019 Sep 19. PMID: 31543384
  13. Pickles JC, Fairchild AR, Stone TJ, Brownlee L, Merve A, Yasin SA, Avery A, Ahmed SW, Ogunbiyi O, Gonzalez Zapata J, Peary AF, Edwards M, Wilkhu L, Dryden C, Ladon D, Kristiansen M, Rowe C, Kurian KM, Nicoll JAR, Mitchell C, Bloom T, Hilton DA, Al-Sarraj S, Doey L, Johns PN, Bridges LR, Chakrabarty A, Ismail A, Rathi N, Syed K, Lammie GA, Limback-Stanic C, Smith C, Torgersen A, Rae F, Hill RM, Clifford SC, Grabovska Y, Williamson D, Clarke M, Jones C, Capper D, Sill M, von Deimling A, Pfister SM, Jones DTW, Hargrave D, Chalker J, Jacques TS. DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study. Lancet Child Adolesc Health. 2019 Nov 27. pii: S2352-4642(19)30342-6. doi: 10.1016/S2352-4642(19)30342-6. [Epub ahead of print] PMID: 31786093
  14. Sievers P, Schrimpf D, Stichel D, Reuss DE, Hasselblatt M, Hagel C, Staszewski O, Hench J, Frank S, Brandner S, Korshunov A, Wick W, Pfister SM, Reifenberger G, von Deimling A, Sahm F, Jones DTW. Posterior fossa pilocytic astrocytomas with oligodendroglial features show frequent FGFR1 activation via fusion or mutation. Acta Neuropathol. 2019 Nov 15. doi: 10.1007/s00401-019-02097-7. [Epub ahead of print]. PMID: 31729570
  15. Sievers P, Appay R, Schrimpf D, Stichel D, Reuss DE, Wefers AK, Reinhardt A, Coras R, Ruf VC, Schmid S, de Stricker K, Boldt HB, Kristensen BW, Petersen JK, Ulhøi BP, Gardberg M, Aronica E, Hasselblatt M, Brück W, Bielle F, Mokhtari K, Lhermitte B, Wick W, Herold-Mende C, Hänggi D, Brandner S, Giangaspero F, Capper D, Rushing E, Wesseling P, Pfister SM, Figarella-Branger D, von Deimling A, Sahm F, Jones DTW. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1. Acta Neuropathol. 2019 Sep;138(3):497-504. doi: 10.1007/s00401-019-02038-4. Epub 2019 Jun 27. PMID: 31250151
  16. Wefers AK, Stichel D, Schrimpf D, Coras R, Pages M, Tauziède-Espariat A, Varlet P, Schwarz D, Söylemezoglu F, Pohl U, Pimentel J, Meyer J, Hewer E, Japp A, Joshi A, Reuss DE, Reinhardt A, Sievers P, Casalini MB, Ebrahimi A, Huang K, Koelsche C, Low HL, Rebelo O, Marnoto D, Becker AJ, Staszewski O, Mittelbronn M, Hasselblatt M, Schittenhelm J, Cheesman E, de Oliveira RS, Queiroz RGP, Valera ET, Hans VH, Korshunov A, Olar A, Ligon KL, Pfister SM, Jaunmuktane Z, Brandner S, Tatevossian RG, Ellison DW, Jacques TS, Honavar M, Aronica E, Thom M, Sahm F, von Deimling A, Jones DTW, Blumcke I, Capper D. Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course. Acta Neuropathol. 2019 Sep 28. doi: 10.1007/s00401-019-02078-w. [Epub ahead of print] PMID: 31563982
  17. Carreno G, Boult JKR, Apps JR, Gonzalez-Meljem JM, Haston S, Guiho R, Stache C, Danielson LS, Koers A, Smith LS, Virasami A, Panousopoulos L, Buchfelder M, Jacques TS, Chesler L, Robinson S, Martinez-Barbera JP. SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma. Endocr Relat Cancer. 2019 Jan 1. pii: ERC-18-0538.R1. doi: 10.1530/ERC-18-0538. PMID:30645190
  18. Buhl JL, Selt F, Hielscher T, Guiho R, Ecker J, Sahm F, Ridinger J, Riehl D, Usta D, Ismer B, Sommerkamp AC, Martinez-Barbera JP, Wefers AK, Remke M, Picard D, Pusch S, Gronych J, Oehme I, van Tilburg CM, Kool M, Kuhn D, Capper D, von Deimling A, Schuhmann MU, Herold-Mende C, Korshunov A, Brummer T, Pfister SM, Jones DTW, Witt O, Milde T. The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma. Clin Cancer Res. 2019 Mar 15;25(6):1851-1866. doi: 10.1158/1078-0432.CCR-18-1965. Epub 2018 Dec 7. PMID: 30530705
  19. Blümcke I, Coras R, Wefers AK, Capper D, Aronica E, Becker A, Honavar M, Stone TJ, Jacques TS, Miyata H, Mühlebner A, Pimentel J, Söylemezoğlu F, Thom M. Challenges in the histopathological classification of ganglioglioma and DNT: microscopic agreement studies and a preliminary genotype-phenotype analysis. Neuropathol Appl Neurobiol. 2019 Feb;45(2):95-107. doi: 10.1111/nan.12522. Epub 2018 Dec 9. Review. PMID: 30326153
  20. Valera ET, McConechy MK, Gayden T, Rivera B, Jones DTW, Wittmann A, Han H, Bareke E, Nikbakht H, Mikael L, Queiroz RG, Suazo VK, Phi JH, Kim SK, Park SH, Fukaya R, Yum MS, Ko TS, de Oliveira RS, Machado HR, Brassesco MS, do Santos AC, Simão GN, Ramalho LNZ, Neder L, Scrideli CA, Tone LG, Majewski J, Jabado N. Methylome analysis and whole-exome sequencing reveal that brain tumors associated with encephalocraniocutaneous lipomatosis are midline pilocytic astrocytomas. Acta Neuropathol. 2018 Oct;136(4):657-660. doi: 10.1007/s00401-018-1898-8. Epub 2018 Aug 24. PMID: 30143858
  21. Sievers P, Stichel D, Schrimpf D, Sahm F, Koelsche C, Reuss DE, Wefers AK, Reinhardt A, Huang K, Ebrahimi A, Hou Y, Pajtler KW, Pfister SM, Hasselblatt M, Stummer W, Schick U, Hartmann C, Hagel C, Staszewski O, Reifenberger G, Beschorner R, Coras R, Keyvani K, Kohlhof P, Diomedi-Camassei F, Herold-Mende C, Giangaspero F, Rushing E, Giannini C, Korshunov A, Jones DTW, von Deimling A. FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. Acta Neuropathol. 2018 Jul 5. doi: 10.1007/s00401-018-1882-3. PMID: 29978331
  22. Deng MY, Sill M, Chiang J, Schittenhelm J, Ebinger M, Schuhmann MU, Monoranu CM, Milde T, Wittmann A, Hartmann C, Sommer C, Paulus W, Gärtner J, Brück W, Rüdiger T, Leipold A, Jaunmuktane Z, Brandner S, Giangaspero F, Nozza P, Mora J, Morales la Madrid A, Cruz Martinez O, Hansford JR, Pietsch T, Tietze A, Hernáiz-Driever P, Stoler I, Capper D, Korshunov A, Ellison DW, von Deimling A, Pfister SM, Sahm F, Jones DTW. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol. 2018 May 15. doi: 10.1007/s00401-018-1865-4. PMID: 29766299
  23. Siegfried A, Rousseau A, Maurage CA, Pericart S, Nicaise Y, Escudie F, Grand D, Delrieu A, Gomez-Brouchet A, Le Guellec S, Franchet C, Boetto S, Vinchon M, Sol JC, Roux FE, Rigau V, Bertozzi AI, Jones DTW, Figarella-Branger D, Uro-Coste E EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity. Brain Pathol. 2018 Apr 21. doi: 10.1111/bpa.12619. PMID: 29679497
  24. Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE, Kratz A, Wefers AK, Huang K, Pajtler KW, Schweizer L, Stichel D, Olar A, Engel NW, Lindenberg K, Harter PN, Braczynski AK, Plate KH, Dohmen H, Garvalov BK, Coras R, Hölsken A, Hewer E, Bewerunge-Hudler M, Schick M, Fischer R, Beschorner R, Schittenhelm J, Staszewski O, Wani K, Varlet P, Pages M, Temming P, Lohmann D, Selt F, Witt H, Milde T, Witt O, Aronica E, Giangaspero F, Rushing E, Scheurlen W, Geisenberger C, Rodriguez FJ, Becker A, Preusser M, Haberler C, Bjerkvig R, Cryan J, Farrell M, Deckert M, Hench J, Frank S, Serrano J, Kannan K, Tsirigos A, Brück W, Hofer S, Brehmer S, Seiz-Rosenhagen M, Hänggi D, Hans V, Rozsnoki S, Hansford JR, Kohlhof P, Kristensen BW, Lechner M, Lopes B, Mawrin C, Ketter R, Kulozik A, Khatib Z, Heppner F, Koch A, Jouvet A, Keohane C, Mühleisen H, Mueller W, Pohl U, Prinz M, Benner A, Zapatka M, Gottardo NG, Driever PH, Kramm CM, Müller HL, Rutkowski S, von Hoff K, Frühwald MC, Gnekow A, Fleischhack G, Tippelt S, Calaminus G, Monoranu CM, Perry A, Jones C, Jacques TS, Radlwimmer B, Gessi M, Pietsch T, Schramm J, Schackert G, Westphal M, Reifenberger G, Wesseling P, Weller M, Collins VP, Blümcke I, Bendszus M, Debus J, Huang A, Jabado N, Northcott PA, Paulus W, Gajjar A, Robinson GW, Taylor MD, Jaunmuktane Z, Ryzhova M, Platten M, Unterberg A, Wick W, Karajannis MA, Mittelbronn M, Acker T, Hartmann C, Aldape K, Schüller U, Buslei R, Lichter P, Kool M, Herold-Mende C, Ellison DW, Hasselblatt M, Snuderl M, Brandner S, Korshunov A, von Deimling A, Pfister SM. DNA methylation-based classification of central nervous system tumours. Nature. 2018 Mar 22;555(7697):469-474. doi: 10.1038/nature26000. Epub 2018 Mar 14. PMID: 29539639
  25. Apps JR, Carreno G, Gonzalez-Meljem JM, Haston S, Guiho R, Cooper JE, Manshaei S, Jani N, Hölsken A, Pettorini B, Beynon RJ, Simpson DM, Fraser HC, Hong Y, Hallang S, Stone TJ, Virasami A, Donson AM, Jones D, Aquilina K, Spoudeas H, Joshi AR, Grundy R, Storer LCD, Korbonits M, Hilton DA, Tossell K, Thavaraj S, Ungless MA, Gil J, Buslei R, Hankinson T, Hargrave D, Goding C, Andoniadou CL, Brogan P, Jacques TS, Williams HJ, Martinez-Barbera JP. Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target. Acta Neuropathol. 2018 May;135(5):757-777. doi: 10.1007/s00401-018-1830-2. Epub 2018 Mar 14. PMID: 29541918
  26. Stone TJ, Rowell R, Jayasekera BAP, Cunningham MO, Jacques TS. Review: Molecular characteristics of long-term epilepsy-associated tumours (LEATs) and mechanisms for tumour-related epilepsy (TRE). Neuropathol Appl Neurobiol. 2018 Feb;44(1):56-69. doi: 10.1111/nan.12459. Review. PMID: 29315734
  27. Stone TJ, Keeley A, Virasami A, Harkness W, Tisdall M, Izquierdo Delgado E, Gutteridge A, Brooks T, Kristiansen M, Chalker J, Wilkhu L, Mifsud W, Apps J, Thom M, Hubank M, Forshew T, Cross JH, Hargrave D, Ham J, Jacques TS. Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours. Acta Neuropathol. 2018 Jan;135(1):115-129. doi: 10.1007/s00401-017-1773-z. Epub 2017 Oct 20. PMID: 29058119
  28. Blumcke I, Spreafico R, Haaker G, Coras R, Kobow K, Bien CG, Pfäfflin M, Elger C, Widman G, Schramm J, Becker A, Braun KP, Leijten F, Baayen JC, Aronica E, Chassoux F, Hamer H, Stefan H, Rössler K, Thom M, Walker MC, Sisodiya SM, Duncan JS, McEvoy AW, Pieper T, Holthausen H, Kudernatsch M, Meencke HJ, Kahane P, Schulze-Bonhage A, Zentner J, Heiland DH, Urbach H, Steinhoff BJ, Bast T, Tassi L, Lo Russo G, Özkara C, Oz B, Krsek P, Vogelgesang S, Runge U, Lerche H, Weber Y, Honavar M, Pimentel J, Arzimanoglou A, Ulate-Campos A, Noachtar S, Hartl E, Schijns O, Guerrini R, Barba C, Jacques TS, Cross JH, Feucht M, Mühlebner A, Grunwald T, Trinka E, Winkler PA, Gil-Nagel A, Toledano Delgado R, Mayer T, Lutz M, Zountsas B, Garganis K, Rosenow F, Hermsen A, von Oertzen TJ, Diepgen TL, Avanzini G; EEBB Consortium. Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery. N Engl J Med. 2017 Oct 26;377(17):1648-1656. doi: 10.1056/NEJMoa1703784. PMID: 29069555
In this video, MD student Maximilian Deng summarizes his latest work that was published in August 2020.
In this video, MD student Maximilian Deng gives us an update on some of the work he has been doing recently in the Jones lab.
In this video, we share with you the progress that has been done in 2019 by the Everest Team.