2. Academic Validation
  3. Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours

Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours

  • Br J Cancer. 2024 Jun 28. doi: 10.1038/s41416-024-02740-5.
Till Seiboldt 1 2 3 4,  Constantia Zeiser 1 2 3 4,  Duy Nguyen 5,  Simay Celikyürekli 1 2 3 6 7,  Sonja Herter 1 2 3 6,  Sara Najafi 1 2 3 7,  Alexandra Stroh-Dege 1 2 3,  Chris Meulenbroeks 8,  Norman Mack 1 3 9,  Rabia Salem-Altintas 1 2 3 4,  Frank Westermann 1 3 10,  Matthias Schlesner 5 11,  Till Milde 1 2 3 7,  Marcel Kool 1 3 8 9 12,  Tim Holland-Letz 13,  Meike Vogler 14 15 16,  Heike Peterziel 1 2 3,  Olaf Witt 1 2 3 7,  Ina Oehme 17 18 19
Affiliations

Affiliations

  • 1 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • 2 Clinical Cooperation Unit Pediatric Oncology (B310), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 3 National Center for Tumor Diseases Heidelberg, Heidelberg, Germany.
  • 4 Faculty of Medicine, Heidelberg University, Heidelberg, Germany.
  • 5 Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 6 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 7 Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
  • 8 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • 9 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 10 Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 11 Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany.
  • 12 University Medical Center Utrecht, Utrecht, the Netherlands.
  • 13 Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 14 Institute for Experimental Pediatric Hematology and Oncology, Goethe-University Frankfurt, Frankfurt, Germany.
  • 15 German Cancer Consortium (DKTK) partner site Frankfurt/Mainz, a partnership between DKFZ and University Hospital Frankfurt, Frankfurt, Germany.
  • 16 University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe-University Frankfurt, Frankfurt, Germany.
  • 17 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. i.oehme@kitz-heidelberg.de.
  • 18 Clinical Cooperation Unit Pediatric Oncology (B310), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany. i.oehme@kitz-heidelberg.de.
  • 19 National Center for Tumor Diseases Heidelberg, Heidelberg, Germany. i.oehme@kitz-heidelberg.de.
PMID: 38942989 DOI: 10.1038/s41416-024-02740-5
Abstract

Background: Certain paediatric nervous system malignancies have dismal prognoses. Retinoic acid (RA) is used in neuroblastoma treatment, and preclinical data indicate potential benefit in selected paediatric brain tumour entities. However, limited single-agent efficacy necessitates combination treatment approaches.

Methods: We performed drug sensitivity profiling of 76 clinically relevant drugs in combination with RA in 16 models (including patient-derived tumouroids) of the most common paediatric nervous system tumours. Drug responses were assessed by viability assays, high-content imaging, and Apoptosis assays and RA relevant pathways by RNAseq from treated models and patient samples obtained through the precision oncology programme INFORM (n = 2288). Immunoprecipitation detected Bcl-2 Family interactions, and zebrafish embryo xenografts were used for in vivo efficacy testing.

Results: Group 3 medulloblastoma (MBG3) and neuroblastoma models were highly sensitive to RA treatment. RA induced differentiation and regulated apoptotic genes. RNAseq analysis revealed high expression of BCL2L1 in MBG3 and BCL2 in neuroblastomas. Co-treatments with RA and Bcl-2/XL inhibitor navitoclax synergistically decreased viability at clinically achievable concentrations. The combination of RA with navitoclax disrupted the binding of Bim to BCL-XL in MBG3 and to Bcl-2 in neuroblastoma, inducing Apoptosis in vitro and in vivo.

Conclusions: RA treatment primes MBG3 and NB cells for Apoptosis, triggered by navitoclax cotreatment.

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