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000169022 037__ $$aDKFZ-2021-01190
000169022 041__ $$aEnglish
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000169022 1001_ $$aLötsch, Daniela$$b0
000169022 245__ $$aTargeting fibroblast growth factor receptors to combat aggressive ependymoma.
000169022 260__ $$aHeidelberg$$bSpringer$$c2021
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000169022 500__ $$a#LA:B062#/2021 Aug;142(2):339-360
000169022 520__ $$aEpendymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.
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000169022 650_7 $$2Other$$aBrain tumor
000169022 650_7 $$2Other$$aEpendymoma
000169022 650_7 $$2Other$$aFGFR
000169022 650_7 $$2Other$$aPediatric cancer
000169022 650_7 $$2Other$$aSmall molecule inhibitors
000169022 7001_ $$aKirchhofer, Dominik$$b1
000169022 7001_ $$aEnglinger, Bernhard$$b2
000169022 7001_ $$aJiang, Li$$b3
000169022 7001_ $$0P:(DE-He78)34b3639de467b2c700920d7cbc3d2110$$aOkonechnikov, Konstantin$$b4$$udkfz
000169022 7001_ $$0P:(DE-He78)61889451052db57c9974789bb68e75e9$$aSenfter, Daniel$$b5$$udkfz
000169022 7001_ $$aLaemmerer, Anna$$b6
000169022 7001_ $$aGabler, Lisa$$b7
000169022 7001_ $$aPirker, Christine$$b8
000169022 7001_ $$aDonson, Andrew M$$b9
000169022 7001_ $$aBannauer, Peter$$b10
000169022 7001_ $$aKorbel, Pia$$b11
000169022 7001_ $$aJaunecker, Carola N$$b12
000169022 7001_ $$0P:(DE-He78)a8c698e0904394407c5261932915daa5$$aHübner, Jens-Martin$$b13$$udkfz
000169022 7001_ $$aMayr, Lisa$$b14
000169022 7001_ $$aMadlener, Sibylle$$b15
000169022 7001_ $$aSchmook, Maria T$$b16
000169022 7001_ $$aRicken, Gerda$$b17
000169022 7001_ $$0P:(DE-He78)5100059e746b377e2e0a37c0e24f6bf7$$aMaaß, Kendra$$b18$$udkfz
000169022 7001_ $$aGrusch, Michael$$b19
000169022 7001_ $$aHolzmann, Klaus$$b20
000169022 7001_ $$aGrasl-Kraupp, Bettina$$b21
000169022 7001_ $$aSpiegl-Kreinecker, Sabine$$b22
000169022 7001_ $$aHsu, Jennifer$$b23
000169022 7001_ $$aDorfer, Christian$$b24
000169022 7001_ $$aRössler, Karl$$b25
000169022 7001_ $$aAzizi, Amedeo A$$b26
000169022 7001_ $$aForeman, Nicholas K$$b27
000169022 7001_ $$aPeyrl, Andreas$$b28
000169022 7001_ $$aHaberler, Christine$$b29
000169022 7001_ $$aCzech, Thomas$$b30
000169022 7001_ $$aSlavc, Irene$$b31
000169022 7001_ $$aFilbin, Mariella G$$b32
000169022 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian W$$b33$$udkfz
000169022 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b34$$udkfz
000169022 7001_ $$aBerger, Walter$$b35
000169022 7001_ $$0P:(DE-He78)a975a4d7d3d59cc6ecc829e98bfe0c15$$aGojo, Johannes$$b36$$eLast author$$udkfz
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