2. Academic Validation
  3. Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir

Enhanced Survival of High-Risk Medulloblastoma-Bearing Mice after Multimodal Treatment with Radiotherapy, Decitabine, and Abacavir

  • Int J Mol Sci. 2022 Mar 30;23(7):3815. doi: 10.3390/ijms23073815.
Marieke Gringmuth 1,  Jenny Walther 2 3,  Sebastian Greiser 2 3,  Magali Toussaint 4,  Benjamin Schwalm 5 6,  Marcel Kool 5 6 7,  Rolf-Dieter Kortmann 1,  Annegret Glasow 1,  Ina Patties 1
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, University of Leipzig, Stephanstraße 9a, 04103 Leipzig, Germany.
  • 2 Fraunhofer Center for Microelectronic and Optical Systems for Biomedicine, Herman-Hollerith-Straße 3, 99099 Erfurt, Germany.
  • 3 Fraunhofer Institute for Cell Therapy and Immunology, Perlickstraße 1, 04103 Leipzig, Germany.
  • 4 Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
  • 5 Hopp Children's Cancer Center (KiTZ), Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
  • 6 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  • 7 Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands.
PMID: 35409174 DOI: 10.3390/ijms23073815
Abstract

Children with high-risk SHH/TP53-mut and Group 3 medulloblastoma (MB) have a 5-year overall survival of only 40%. Innovative approaches to enhance survival while preventing adverse effects are urgently needed. We investigated an innovative therapy approach combining irradiation (RT), decitabine (DEC), and abacavir (ABC) in a patient-derived orthotopic SHH/TP53-mut and Group 3 MB mouse model. MB-bearing mice were treated with DEC, ABC and RT. Mouse survival, tumor growth (BLI, MRT) tumor histology (H/E), proliferation (Ki-67), and endothelial (CD31) staining were analyzed. Gene expression was examined by microarray and RT-PCR (Ki-67, VEGF, CD31, CD15, CD133, nestin, CD68, IBA). The RT/DEC/ABC therapy inhibited tumor growth and enhanced mouse survival. Ki-67 decreased in SHH/TP53-mut MBs after RT, DEC, RT/ABC, and RT/DEC/ABC therapy. CD31 was higher in SHH/TP53-mut compared to Group 3 MBs and decreased after RT/DEC/ABC. Microarray analyses showed a therapy-induced downregulation of cell cycle genes. By RT-PCR, no therapy-induced effect on stem cell fraction or immune cell invasion/activation could be shown. We showed for the first time that RT/DEC/ABC therapy improves survival of orthotopic SHH/TP53-mut and Group 3 MB-bearing mice without inducing adverse effects suggesting the potential for an Adjuvant application of this multimodal therapy approach in the human clinic.

Keywords

T2 mapping; abacavir; bioluminescence imaging; decitabine; gene expression microarray; in vivo study; magnetic resonance imaging; medulloblastoma; radiation.

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