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  • Ecker, Jonas  (6)
  • Peterziel, Heike  (6)
  • 1
    Online Resource
    Online Resource
    Class I HDAC inhibition reduces DNA damage repair capacity of MYC-amplified medulloblastoma cells
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Neuro-Oncology
    Details
    In: Journal of Neuro-Oncology, Springer Science and Business Media LLC
    Abstract: MYC -driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC -driven MB to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. In this study we characterize the transcriptional effects of class I HDACi in MYC -driven MB and explore beneficial drug combinations. Methods MYC -amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile were quantified on a microarray. Bioinformatic assessment led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested for synergy with entinostat in WST-8 metabolic activity assays in a 5 × 5 combination matrix design. Synergy was validated in cell count and flow cytometry experiments. The effect of entinostat and olaparib on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry. Results Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat selectively in MYC -amplified MB cells, leading to increased cell death, decreased viability and increased formation of double strand breaks, as well as increased sensitivity to additional induction of DNA damage by doxorubicin. Non- MYC -amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment. Conclusion Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC -driven Group 3 MB.
    Type of Medium: Online Resource
    ISSN: 0167-594X , 1573-7373
    URL: Article
    DOI: 10.1007/s11060-023-04445-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2007293-4
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  • 2
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    MBRS-19. SYNERGISM OF HDAC AND PARP INHIBITORS IN MYC-DRIVEN GROUP 3 MEDULLOBLASTOMA CELLS
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii401-iii401
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii401-iii401
    Abstract: Patients with MYC-driven Group 3 medulloblastoma (MB) show particularly poor outcome. It was previously shown that MYC-driven MBs are highly sensitive to class I histone deacetylase inhibition (HDACi). We studied the molecular effects of the class I HDACi entinostat in MYC-driven MB cells to identify potentially synergistic drug combinations, prioritizing drug clinical availability to enable clinical translation. Gene expression profiles of the MYC-amplified group 3 MB cell line HD-MB03 treated with entinostat were analyzed using bioinformatic approaches, identifying 29 altered biomechanisms. Overlay with a translational drug library of n=76 compounds resulted in 44 compounds targeting 9 biomechanisms. Filtering for publications supporting each drug′s role in MYC-driven entities, or functional interaction with HDACs, without publication of this combination in MBs, resulted in 5 compounds (olaparib, idasanutlin, ribociclib, selinexor, vinblastine). Synergism testing identified olaparib as the drug with the strongest synergism. Validation of the combination olaparib and entinostat by p.H2AX and PI staining as well as trypan blue exclusion showed increased double strand breaks (DSBs), increased cell death, loss of viability and cell numbers. Selectivity of MYC-amplified MB cells was shown by comparison to MYC-non amplified cell lines, which showed higher IC50s, and reacted with cell cycle arrest as opposed to cell death to the combination treatment. The role of HDACis in DNA damage repair was confirmed by increased DSBs when entinostat was added to the combination of olaparib with doxorubicin. Our study identified olaparib as a potential combination partner with entinostat for the treatment of MYC-driven Group 3 MB.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.535
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 3
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    Key Pharmacokinetic Parameters of 74 Pediatric Anticancer Drugs Providing Assistance in Preclinical Studies
    Wiley ; 2023
    In:  Clinical Pharmacology & Therapeutics Vol. 114, No. 4 ( 2023-10), p. 904-913
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    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 114, No. 4 ( 2023-10), p. 904-913
    Abstract: Novel drug treatments for pediatric patients with cancer are urgently needed. Success of drug development in pediatric oncology has been promising, but many drugs still fail in translation from preclinical to clinical phases. To increase the translational potential, several improvements have been implemented, including the use of clinically achievable concentrations in the drug testing phase. Although pharmacokinetic (PK) parameters of numerous investigated drugs are published, a comprehensive PK overview of the most common drugs in pediatric oncology could guide preclinical trial design and improve the translatability into clinical trials. A review of the literature was conducted for PK parameters of 74 anticancer drugs, from the drug sensitivity profiling library of the INdividualized Therapy FOr Relapsed Malignancies in Childhood (INFORM) registry. PK data in the pediatric population were reported and complemented by adult parameters when no pediatric data were available. In addition, blood–brain barrier (BBB)‐penetration assessment of drugs was provided by using the BBB score. Maximum plasma concentration was available for 73 (97%), area under the plasma concentration‐time curve for 69 (92%), plasma protein binding for 66 (88%), plasma half‐life for 57 (76%), time to maximum concentration for 54 (72%), clearance for 52 (69%), volume of distribution for 37 (49%), lowest plasma concentration reached by the drug before the next dose administration for 21 (28%), and steady‐state concentration for 4 (5%) of drugs. Pediatric PK data were available for 48 (65%) drugs. We provide a comprehensive review of PK data for 74 drugs studied in pediatric oncology. This data set can serve as a reference to design experiments more closely mimicking drug PK conditions in patients, and may thereby increase the probability of successful clinical translation.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v114.4
    DOI: 10.1002/cpt.3002
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2040184-X
    SSG: 15,3
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  • 4
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    PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
    Springer Science and Business Media LLC ; 2021
    In:  Acta Neuropathologica Vol. 142, No. 5 ( 2021-11), p. 841-857
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    In: Acta Neuropathologica, Springer Science and Business Media LLC, Vol. 142, No. 5 ( 2021-11), p. 841-857
    Abstract: Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms ( n  = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1 -fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1 : PATZ1 or EWSR1 : PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2 , GATA2 and IGF2 . Drug screening performed on the MN1 : PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
    Type of Medium: Online Resource
    ISSN: 0001-6322 , 1432-0533
    URL: Article
    DOI: 10.1007/s00401-021-02354-8
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1458410-4
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  • 5
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    EMBR-11. SYNERGISTIC DRUG COMBINATIONS FOR THE TREATMENT OF MYC AMPLIFIED GROUP 3 MEDULLOBLASTOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i7-i8
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    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i7-i8
    Abstract: Medulloblastoma (MB) is a highly aggressive brain tumour in children. Patients with Group 3 MB harbouring a MYC-amplification (subtype II) show a particularly poor outcome despite high-intensity multimodal therapy. We and others have previously shown that MYC amplified Group 3 MB cells are highly susceptible towards treatment with class I histone deacetylase (HDAC) inhibitors such as entinostat. However, in clinical trials HDACi as a monotherapy show only modest efficacy in solid tumours. We propose to increase the efficacy of class I HDACi by drug combinations. Methods To identify synergistic drug combinations (entinostat + X) for the treatment of MYC amplified MB we performed a drug screen with a library of n=75 clinically available compounds as single agents and in combination with entinostat in n=3 MYC amplified vs. n=1 MYC-non amplified cell lines. Synergistic behaviour of the six most promising drug combinations was validated by metabolic activity assays, cell count experiments and gene expression profiling. Synergy was assessed by the Loewe additivity model using a combination of ray design and checkerboard matrix. Results The drug screen revealed n=20/75 drugs that were particularly effective (drug sensitivity score ≥10) in combination with entinostat treatment in all three MYC amplified cell lines. Synergy assessment of the top n=6 drugs confirmed strong synergistic activity with entinostat for n=2 drugs (navitoclax, irinotecan). The BCL-2 family inhibitor navitoclax showed the most robust synergy with entinostat in subsequent validation experiments. Conclusion Several drugs either clinically available or currently in clinical trials, including the BCL-2/Xl/w inhibitor navitoclax, show promising effects in a combination therapy with entinostat for the treatment of MYC amplified Group 3 MB.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.029
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 6
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    Combination drug screen identifies synergistic drug interaction of BCL-XL and class I histone deacetylase inhibitors in MYC-amplified medulloblastoma cells
    Springer Science and Business Media LLC ; 2024
    In:  Journal of Neuro-Oncology Vol. 166, No. 1 ( 2024-01), p. 99-112
    Details
    In: Journal of Neuro-Oncology, Springer Science and Business Media LLC, Vol. 166, No. 1 ( 2024-01), p. 99-112
    Abstract: Patients with MYC -amplified Group 3 medulloblastoma (MB) (subtype II) show poor progression-free survival rates. Class I histone deacetylase inhibitors (HDACi) are highly effective for the treatment of MYC -amplified MB in vitro and in vivo. Drug combination regimens including class I HDACi may represent an urgently needed novel treatment approach for this high risk disease. Methods A medium-throughput in vitro combination drug screen was performed in three MYC -amplified and one non- MYC -amplified MB cell line testing 75 clinically relevant drugs alone and in combination with entinostat. The drug sensitivity score (DSS) was calculated based on metabolic inhibition quantified by CellTiter-Glo. The six top synergistic combination hits were evaluated in a 5 × 5 combination matrix and a seven-ray design. Synergy was validated and characterized by cell counts, caspase-3-like-activity and poly-(ADP-ribose)-polymerase-(PARP)-cleavage. On-target activity of drugs was validated by immunoprecipitation and western blot. BCL-XL dependency of the observed effect was explored with siRNA mediated knockdown of BCL2L1 , and selective inhibition with targeted compounds (A-1331852, A-1155463). Results 20/75 drugs effectively reduced metabolic activity in combination with entinostat in all three MYC -amplified cell lines (DSS ≥ 10). The combination entinostat and navitoclax showed the strongest synergistic interaction across all MYC -amplified cell lines. siRNA mediated knockdown of BCL2L1 , as well as targeted inhibition with selective inhibitors showed BCL-XL dependency of the observed effect. Increased cell death was associated with increased caspase-3-like-activity. Conclusion Our study identifies the combination of class I HDACi and BCL-XL inhibitors as a potential new approach for the treatment of MYC -amplified MB cells. Graphical abstract
    Type of Medium: Online Resource
    ISSN: 0167-594X , 1573-7373
    URL: Article
    DOI: 10.1007/s11060-023-04526-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2024
    detail.hit.zdb_id: 2007293-4
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