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

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii275-iii275
Author(s):  
Minh-Huy Tran ◽  
Kuo-Sheng Wu ◽  
Che-Chang Chang ◽  
Tai-Tong Wong
Keyword(s):  
Protein Synthesis ◽  
Tumor Cell ◽  
Proteasome Inhibitor ◽  
Normal Brain ◽  
Proteasome Degradation ◽  
Orthotopic Xenograft ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Encoding Genes

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.

scholarly journals Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 752
Author(s):  
Huy Minh Tran ◽  
Kuo-Sheng Wu ◽  
Shian-Ying Sung ◽  
Chun Austin Changou ◽  
Tsung-Han Hsieh ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tumor Cell ◽  
Proteasome Inhibitor ◽  
Gene Set Enrichment Analysis ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Proteasome Degradation ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

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. 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. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs 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 three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

scholarly journals Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors

2017 ◽  
Vol 6 ◽  
pp. 22-30 ◽  
Author(s):  
Adam W. Studebaker ◽  
Brian J. Hutzen ◽  
Christopher R. Pierson ◽  
Kellie B. Haworth ◽  
Timothy P. Cripe ◽  
...  
Keyword(s):  
Herpes Virus ◽  
Orthotopic Xenograft ◽  
Atypical Teratoid ◽  
Group 3 ◽  
Herpès Virus ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

scholarly journals ATRT-09. IDENTIFICATION OF HUB GENES IN ATYPICAL TERATOID/RHABDOID TUMORS BY MULTIPLE-MICROARRAY ANALYSIS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii277-iii277
Author(s):  
Wei Liu ◽  
Yi Chai ◽  
Junhua Wang ◽  
Yuqi Zhang
Keyword(s):  
Gene Expression ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Malignant Neoplasms ◽  
Pathway Enrichment Analysis ◽  
Normal Brain ◽  
Hub Genes ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) are rare, highly malignant neoplasms arising in infants and young children. However, the biological basis of ATRTs remains poorly understood. In the present study, we employed integrated bioinformatics to investigate the hub genes and potential molecular mechanism in ATRT. METHODS Three microarray datasets, GSE35943, GSE6635 and GSE86574, were downloaded from Gene Expression Omnibus (GEO) which contained a total of 79 samples including 32 normal brain tissue samples and 47 ATRT samples. The RobustRankAggreg method was employed to integrate the results of these gene expression datasets to obtain differentially expressed genes (DEGs). The GO function and KEGG pathway enrichment analysis were conducted at the Enrichr database. The hub genes were screened according to the degree using Cytoscape software. Finally, transcription factor (TF) of hub genes were obtained by the NetworkAnalyst algorithm. RESULTS A total of 297 DEGs, consisting of 94 downregulated DEGs and 103 upregulated DEGs were identified. Functional enrichment analysis revealed that these genes were associated with cell cycle, p53 signaling pathway and DNA replication. Protein-protein interaction (PPI) network analysis revealed that CDK1, CCNA2, BUB1B, CDC20, KIF11, KIF20A, KIF2C, NCAPG, NDC80, NUSAP1, PBK, RRM2, TPX2, TOP2A and TTK were hub genes and these genes could be regulated by MYC, SOX2 and KDM5B according to the results of TF analysis. CONCLUSIONS Our study will improve the understanding of the molecular mechanisms and provide novel therapeutic targets for ATRT.

scholarly journals Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors

2021 ◽  
Vol 9 (10) ◽  
pp. e003404
Author(s):  
Ana Marcu ◽  
Andreas Schlosser ◽  
Anne Keupp ◽  
Nico Trautwein ◽  
Pascal Johann ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Hla Ligandome

BackgroundAtypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells.MethodsHere, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM.ResultsComparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors.ConclusionsThese findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.

scholarly journals NATURAL AND CRYPTIC PEPTIDES DOMINATE THE IMMUNOPEPTIDOME OF ATYPICAL TERATOID RHABDOID TUMORS

2021 ◽  
Author(s):  
Ana Marcu ◽  
Andreas Schlosser ◽  
Anne Keupp ◽  
Nico Trautwein ◽  
Pascal Johann ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
Therapeutic Vaccines ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Hla Ligandome

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS-tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear, which epitopes T-cells might recognize on AT/RT cells. Here, we report a comprehensive MS-based analysis of naturally presented HLA-class-I and class-II ligands on 23 AT/RTs. Comparative HLA ligandome analysis of the HLA-ligandome revealed 55 class-I and 139 class-II tumor-exclusive peptides. No peptide originated from the SMARCB1-region. In addition, 61 HLA-class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas but no concordance was found with extracranial tumors. More than 80% of AT/RT-exclusive peptides were able to successfully prime CD8+ T-cells, whereas naturally occurring memory responses in AT/RT-patients could only be detected for class-II epitopes. Interestingly, >50% of AT/RT-exclusive class-II ligands were also recognized by T-cells from glioblastoma patients but not from healthy donors. These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA-class-I and class-II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.

scholarly journals ATRT-20. CDK7 INHIBITION IN AT/RT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii279-iii280
Author(s):  
Andrew Morin ◽  
Bethany Veo ◽  
Susan Fosmire ◽  
Michele Crespo ◽  
Shadi Zahedi ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Cell Cycle Checkpoints ◽  
Normal Brain ◽  
The Novel ◽  
Loss Of Function ◽  
Genomic Landscape ◽  
Atypical Teratoid ◽  
Xenograft Models ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are characterized by loss-of-function mutations in the SMARCB1 component (and less commonly SMARCA4) of the SWI/SNF chromatin-remodeling complex. AT/RT demonstrate an overall silent genomic landscape with epigenetic dysregulation of the genome. CDK7 is a key transcriptional regulator that preferentially phosphorylates the Ser5 and Ser7 positions on RNA Polymerase C terminal domain and is involved early in transcription. In tumor cells, CDK7 is enriched at super enhancers which preferentially regulate genes involved in cell transformation, and expressed at significantly higher levels in transformed tissues than the surrounding normal brain. Our preliminary data shows that CDK7 is expressed in a number of AT/RT tumor cell lines and patient-derived tumor cultures, and that loss of CDK7 function though exposure to the novel CDK7 inhibitor THZ2 results in lack of proliferation at lower doses, and caspase-mediated apoptosis at higher concentrations. shRNA-based inhibition confirms that this effect is due specifically to loss of CDK7. RNA sequencing of cells treated with lower doses of THZ2 show significant alterations in transcript expression consistent with altered balance between antagonistic SWI/SNF and PRC2 chromatin-modeling complex activities, as well as alterations in DNA damage response pathways, cell cycle checkpoints, miRNA transcription, and numerous proliferative factors. THZ2 penetrates the blood brain barrier (BBB), is well tolerated, and results in prolonged survival in murine xenograft models of AT/RT. CDK7 inhibition also synergizes with a number of currently-approved oncology drugs, as well as with ionizing radiation, in order to inhibit AT/RT growth and viability.

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