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      ATRT-01. UPREGULATION OF PROTEIN SYNTHESIS AND PROTEASOME DEGRADATION CONFERS SENSITIVITY TO PROTEASOME INHIBITOR BORTEZOMIB IN MYC-ATYPICAL TERATOID/RHABDOID TUMORS

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          Abstract

          BACKGROUND

          Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ.

          METHODS

          We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. The expressions of proteasome-encoding genes were compared among this paired model as well as between the 24 human ATRT samples and normal brain tissues. The antitumor effect of BTZ was evaluated in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12, and CHLA-266) and in the orthotopic xenograft models of Re1-P6 cell.

          RESULTS

          Concomitant upregulation of the Myc pathway, protein synthesis, and proteasome degradation were identified in recurrent ATRTs. In ATRTs, the proteasome-encoding genes were highly expressed compared with in normal brain tissues, correlated with the malignancy of tumor cells, and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in in vitro drug tests. Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice.

          CONCLUSIONS

          Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

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          Author and article information

          Journal
          Neuro Oncol
          Neuro Oncol
          neuonc
          Neuro-Oncology
          Oxford University Press (US )
          1522-8517
          1523-5866
          December 2020
          04 December 2020
          04 December 2020
          : 22
          : Suppl 3 , Abstracts from the 19th International Symposium on Pediatric Neuro-Oncology (ISPNO 2020)
          : iii275
          Affiliations
          [1 ] International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
          [2 ] Department of Neurosurgery, University of Medicine and Pharmacy at Ho Chi Minh City , Ho Chi Minh City, Vietnam
          [3 ] Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei, Taiwan
          [4 ] The Ph,D, Program for Translational Medicine, Taipei Medical University , Taipei, Taiwan
          [5 ] Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University , Taipei, Taiwan
          [6 ] Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University , Taipei, Taiwan
          Article
          noaa222.001
          10.1093/neuonc/noaa222.001
          7715207
          3932c79e-83d3-4c4c-8d70-4563bae562ef
          © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

          History
          Page count
          Pages: 1
          Categories
          Atypical Teratoid/Rhabdoid Tumors
          AcademicSubjects/MED00300
          AcademicSubjects/MED00310

          Oncology & Radiotherapy
          Oncology & Radiotherapy

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