Klin Padiatr 2023; 235(06): 380
DOI: 10.1055/s-0043-1774770
Abstracts

Preventing recurrence: targeting molecular mechanisms driving tumor growth rebound after MAPKi withdrawal in pediatric low-grade glioma

Authors

  • D Kocher

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    2   Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany
    4   Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

  • F Selt

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    2   Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany
    5   KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

  • G Valinciute

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    2   Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany

  • M Langhammer

    6   Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg

  • J Zaman

    4   Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
    7   Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
    8   Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

  • D Vonhören

    9   Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    10   Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany

  • R Guiho

    11   Developmental Biology and Cancer Programme, Birth Defects Research Centre, Institute of Child Health Great Ormond Street Hospital, University College London, 30 Guilford Street, London, WC1N 1EH, UK

  • J P Martinez-Barbera

    11   Developmental Biology and Cancer Programme, Birth Defects Research Centre, Institute of Child Health Great Ormond Street Hospital, University College London, 30 Guilford Street, London, WC1N 1EH, UK

  • S Halbach

    6   Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg

  • A von Deimling

    7   Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
    8   Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

  • S Pusch

    7   Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany
    8   Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

  • S M Pfister

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany
    5   KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
    12   Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

  • DT W Jones

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    13   Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

  • T Brummer

    6   Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg
    14   Centre for Biological Signaling Studies BIOSS, University of Freiburg, Freiburg, Germany
    15   German Consortium for Translational Cancer Research (DKTK), Freiburg, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany

  • O Witt

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    2   Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany
    5   KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

  • T Milde

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    2   Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany
    5   KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

  • R Sigaud

    1   Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
    2   Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
    3   National Center for Tumor Diseases (NCT), Heidelberg, Germany
Further Information
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Pediatric low-grade gliomas, the most common primary brain tumors in children, are mainly driven by alterations in the MAPK pathway. While patients often benefit from MAPK-inhibitors during treatment, tumor rebound may occur once treatment is stopped, constituting a significant clinical challenge.

BT-40, patient-derived cells with molecular features of pleomorphic xanthoastrocytoma (BRAFV600E, CDKN2Adel), were used to model the rebound growth in vitro, based on viable cell counts in response to treatment and withdrawal of the clinically relevant BRAFV600E-specific inhibitor dabrafenib and standard-of-care chemotherapy as a reference. Based on the observed cell-regrowth and MAPK signaling reactivation pattern (WB- and qPCR-analysis), key-timepoints during withdrawal were identified and further analyzed through RNAseq.

BT-40 cell regrowth was faster after dabrafenib withdrawal compared to chemotherapy withdrawal. MAPK pathway activity showed a transient overactivation upon treatment withdrawal before going back to baseline. Furthermore, single-sample geneset enrichment analysis and GO-Term analysis of upregulated genes upon dabrafenib treatment and withdrawal showed significant enrichment of cytokine-related signaling. This is associated with increased expression of 37 cytokines. Phospho-/proteomics analyses to validate this finding is currently underway.

The earlier cell regrowth after dabrafenib withdrawal compared to chemotherapy withdrawal matches clinical observations, making the model suitable to study the rebound. Gene expression analysis showed enrichment of cytokine activity upon dabrafenib treatment and withdrawal, potentially driving cell rebound growth. Protein expression and secretion of significantly upregulated cytokines is being investigated to identify potential rebound-breaking targets, which will be further investigated in vitro and in vivo using BT-40 as well as additional PXA models.


Publication History

Article published online:
09 November 2023

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