David T. W. Jones, PhD
Group leader "Pediatric glioma research"
Hopp Children's Cancer Center Heidelberg
Im Neuenheimer Feld 280
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.
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
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
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
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
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
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
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
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