Peer-reviewed article
ATRT-01. UPREGULATION OF PROTEIN SYNTHESIS AND PROTEASOME DEGRADATION CONFERS SENSITIVITY TO PROTEASOME INHIBITOR BORTEZOMIB IN MYC-ATYPICAL TERATOID/RHABDOID TUMORS
Tran M, Wu K, Chang C, Wong T ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a laboratory and preclinical study of a drug candidate (bortezomib) for treating atypical teratoid rhabdoid tumors, a rare brain cancer in infants. The research uses cell lines and mouse models to test whether the drug can inhibit tumor growth. While the work concerns a serious disease affecting young children, it is basic biomedical research rather than an evaluation of child health or well-being interventions in real-world settings.
Key points
- Myc-driven atypical teratoid rhabdoid tumors show upregulation of protein synthesis and proteasome degradation pathways
- Bortezomib inhibited tumor cell proliferation and induced apoptosis in three human Myc-ATRT cell lines
- The drug inhibited tumor growth and prolonged survival in orthotopic xenograft mouse models
- Proteasome-encoding genes were highly expressed in ATRTs compared to normal brain tissue
Limitations
This is preclinical research using cell lines and animal models only; it provides no evidence of efficacy or safety in children with ATRT. No human trial data are presented, and translation to clinical benefit remains unproven.
Abstract
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.