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  • Milde, Till  (7)
  • Pfister, Stefan M  (7)
  • Usta, Diren  (7)
  • 2020-2024  (7)
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  • 2020-2024  (7)
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  • 1
    Online Resource
    Online Resource
    LGG-27. Molecular implications of mitogen-activated protein kinase pathway inhibition by the MEK inhibitor trametinib in BRAF-fusion-driven pediatric pilocytic astrocytoma
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i94-i94
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i94-i94
    Abstract: Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by driving alterations in the mitogen-activated protein kinase (MAPK) pathway, leading to its constitutive activation and modulating the balance between cell proliferation and oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP) factors. This makes PA susceptible to MAPK inhibitor (MAPKi) therapies, which show encouraging results in phase 1/2 clinical trials. However, little is known about the molecular implications of MAPK inhibition in PA. The DKFZ-BT66 cell line, derived from a primary KIAA:BRAF-fusion positive PA, was used as a model system. DKFZ-BT66 were treated with the MEKi trametinib for different durations in both proliferative and senescent states. Gene expression was analyzed by gene expression profiling and protein expression/phospho-regulation by data-dependent mass spectrometry followed by label-free quantitative analysis. A time course analysis based on differentially expressed genes and phosphorylated proteins was performed, followed by a single-sample gene set enrichment analysis (ssGSEA) and kinase substrate enrichment analysis, respectively. Differential gene expression analysis revealed that MEK inhibition led to the inhibition of the OIS/SASP gene programs in senescent DKFZ-BT66, with downregulation of key OIS/SASP partners such as IL1B on the protein level. This functionally translated into a de-sensitization of these cells towards the senolytic agent navitoclax. ssGSEA showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including FGFR, NTRK and TGFB pathways) were upregulated, in both proliferating and senescent DKFZ-BT66. This data indicates that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators in proliferating and senescent PA cells, identifying putative co-targets that could help increase treatment’s efficacy. Validation of these targets by post-translational modification enrichment analysis of the phospho-proteomics dataset is ongoing.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.341
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 2
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    Online Resource
    LGG-03. EXPLORING THE SIGNALING NETWORK INVOLVED IN MAPK PATHWAY INHIBITION BY THE MEK INHIBITOR TRAMETINIB IN BRAF-FUSION-DRIVEN PEDIATRIC PILOCYTIC ASTROCYTOMA
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i55-i55
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i55-i55
    Abstract: Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by MAPK pathway alterations, leading to its constitutive activation and modulating the balance between proliferation and oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP). Little is known about the molecular implications of MAPK pathway inhibition in the proliferating and senescent tumor compartments. METHODS DKFZ-BT66 cells derived from a primary KIAA:BRAF-fusion positive PA cell line and BT40 cells derived from pleomorphic xanthoastrocytoma with a BRAFV600E mutation and CDKN2A/B deletion, were used as model systems. RNA-sequencing and phospho-/proteomic datasets were generated in both the proliferative and senescent cells, and treated with the MEKi trametinib for different time-spans. A multi-omics factor analysis tool (MEFISTO) was used to identify key OIS/proliferation effectors. RESULTS Differential gene expression analysis revealed that MEK inhibition leads to the inhibition of the OIS/SASP gene program in senescent DKFZ-BT66. In addition, the protein level of several SASP factors was decreased. This translated in reduced sensitivity towards senolytics drugs, indicating inhibition of senescence features upon MEKi. MEFISTO analysis allowed to identify key transcription factors, genes and proteins involved in MAPK-induced OIS in the senescent PA cells, that were mapped using a prior knowledge network approach. Finally, single sample geneset enrichment analysis showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including several RTK pathways) were predicted to be upregulated, in both proliferating and senescent cells. CONCLUSION This data suggests that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators, identifying putative co-targets for the treatment of PA. Further validation of the targetability of these pathways is pending. Furthermore, the identification of the MAPK-related OIS/SASP genes provide insight about the regulation of OIS/SASP by the MAPK pathway.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.213
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 3
    Online Resource
    Online Resource
    LGG-04. MULTIOMIC ANALYSIS OF MAPK PATHWAY ACTIVITY IN PEDIATRIC PILOCYTIC ASTROCYTOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i31-i32
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i31-i32
    Abstract: Pilocytic astrocytomas (PA) are the most common pediatric brain tumors. They are characterized by MAPK pathway alterations, leading to its constitutive activation and modulating the balance between cell proliferation and the oncogene-induced senescence (OIS) sustained by senescence-associated secretory phenotype (SASP) factors. This makes PA suitable for MAPK inhibitor (MAPKi) therapies, showing encouraging results in phase 1/2 clinical trials. Little is known about the molecular implications of MAPK downregulation in the proliferating and senescent compartments. Methods DKFZ-BT66 PA cells derived from a primary KIAA:BRAF-fusion positive PA cell line, were used as model system. Gene expression and phospho-proteomic datasets were generated from DKFZ-BT66 cells, in both the proliferative and senescent states, and treated with the MEKi trametinib for different time-spans. A time course analysis based on differentially expressed genes was performed, followed by a single-sample gene set enrichment analysis (ssGSEA). Analysis of the phospho-proteomic data is ongoing. Results Differential gene expression analysis revealed that MEK inhibition leads to the inhibition of the OIS-SASP gene program in senescent DKFZ-BT66. ssGSEA showed that most MAPK-related signatures were downregulated upon MEKi treatment, while pathways related to upstream MAPK activators (including FGFR, NTRK and TGFB pathways) were upregulated, in both proliferating and senescent DKFZ-BT66. Genes regulated by the MAPK pathway and involved in OIS-SASP were identified by analyzing genes differentially regulated between proliferating and senescent DKFZ-BT66, and modulated upon MEKi treatment. Conclusion This data suggests that MAPKi reverses OIS in senescent PA cells, while inducing the activation of MAPK upstream regulators in proliferating and senescent PA cells, identifying putative co-targets that could help prevent growth rebound upon MAPKi withdrawal. Furthermore, the identification of the MAPK-related OIS-SASP genes provide insight about the regulation of OIS-SASP by the MAPK pathway. Validation of this data with the ongoing phospho-proteomic analysis and in primary samples is needed.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.128
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 4
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    Online Resource
    LGG-02. DRUG-CLASS SPECIFIC GENE-BASED MAPK SENSITIVITY SCORES (MSS) PREDICT SENSITIVITY TO MAPK INHIBITORS AND IDENTIFY IMMUNE INFILTRATION AS PUTATIVE TARGET IN PEDIATRIC LOW-GRADE GLIOMAS
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i55-i55
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i55-i55
    Abstract: Pediatric low-grade gliomas (pLGG), the most common brain tumors in children, are driven by alterations in the MAPK pathway. Several clinical trials have shown the potential for MAPK inhibitors (MAPKi) treatment in pLGG. However, the range of response is broad, even within entities sharing the same driving genetic MAPK alteration. A predictive stratification tool is needed to identify patients that will be more likely to benefit from MAPKi therapy. METHODS We generated gene-expression-based MAPKi sensitivity scores (MSS) for each MAPKi class (BRAFi, MEKi, ERKi), based on MAPK-related genes differentially regulated between MAPKi sensitive and non-sensitive cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Single sample Gene Set Enrichment Analysis (ssGSEA) was used to measure and validate our MSSs in the GDSC dataset and an independent PDX dataset (XevaDB). The validated signatures were tested in a pLGG-specific background, using gene expression data from PA cell lines and primary pLGG samples. RESULTS Our MSS could differentiate MAPKi sensitive cells in the GDSC dataset, and significantly correlated with MAPKi response in the XevaDB PDX dataset. The MSS were able to differentiate glioma entities with differing MAPK alterations from non-MAPK altered entities, and showed the highest scores in pLGG. The MSSs were heterogeneous within pLGG entities with a common MAPK alteration, as observed in MAPKi clinical studies. Intriguingly, a strong correlation between our MSS and the predicted immune cell infiltration rate, as determined by the Estimate score, was observed and confirmed in a pLGG scRNA sequencing dataset. CONCLUSION These data demonstrate the relevance of gene-expression signatures to predict response to MAPKi treatment in pLGG, and will be further investigated in a prospective manner in upcoming clinical trials. In addition, our data could suggest a role of immune infiltration in the response to MAPKi in pLGG that warrants further validation.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.212
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 5
    Online Resource
    Online Resource
    LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii369-iii369
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_3 ( 2020-12-04), p. iii369-iii369
    Abstract: Pilocytic astrocytomas (PAs) and other pediatric low-grade gliomas (pLGGs) exhibit aberrant activation of the MAPK signaling pathway caused by genetic alterations, most commonly KIAA1549:BRAF fusions, BRAF V600E and NF1 mutations. In such a single-pathway disease, novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for treatment. We developed an assay suitable for pre-clinical testing of MAPKi in pLGGs, aiming at the identification of novel MAPK pathway suppressing synergistic drug combinations. We generated a reporter plasmid (pDIPZ) expressing destabilized firefly luciferase driven by a MAPK-responsive ELK-1-binding element, packaged in a lentiviral vector system. We stably transfected pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively. Measurement of MAPK pathway activity was performed using the luciferase reporter. pERK protein levels were detected for validation. We performed a screen of a MAPKi library and calculated Combination Indices of selected combinations. The MAPKi library screen revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and second generation RAF inhibitors. Synergistic effects in both BRAF-fusion and BRAFV600E mutation backgrounds were observed following combination treatments with different MAPKi classes (RAFi/MEKi, & gt; RAFi/ERKi & gt; MEKi/ERKi). We have generated a novel reporter assay for medium- to high-throughput pre-clinical drug testing of MAPKi in pLGG cell lines. MEK, ERK and next-generation RAF inhibitors were confirmed as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. Synergistic suppression of MAPK pathway activity upon combination treatments was revealed using our assay in addition.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa222.399
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    Online Resource
    Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. 2 ( 2021-02-25), p. 226-239
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. 2 ( 2021-02-25), p. 226-239
    Abstract: The sensitivity of myelocytomatosis oncogene (MYC) amplified medulloblastoma to class I histone deacetylase (HDAC) inhibition has been shown previously; however, understanding the underlying molecular mechanism is crucial for selection of effective HDAC inhibitors for clinical use. The aim of this study was to investigate the direct molecular interaction of MYC and class I HDAC2, and the impact of class I HDAC inhibition on MYC function. Methods Co-immunoprecipitation and mass spectrometry were used to determine the co-localization of MYC and HDAC2. Chromatin immunoprecipitation (ChIP) sequencing and gene expression profiling were used to analyze the co-localization of MYC and HDAC2 on DNA and the impact on transcriptional activity in primary tumors and a MYC amplified cell line treated with the class I HDAC inhibitor entinostat. The effect on MYC was investigated by quantitative real-time PCR, western blot, and immunofluorescence. Results HDAC2 is a cofactor of MYC in MYC amplified medulloblastoma. The MYC-HDAC2 complex is bound to genes defining the MYC-dependent transcriptional profile. Class I HDAC inhibition leads to stabilization and reduced DNA binding of MYC protein, inducing a downregulation of MYC activated genes (MAGs) and upregulation of MYC repressed genes (MRGs). MAGs and MRGs are characterized by opposing biological functions and by distinct enhancer-box distribution. Conclusions Our data elucidate the molecular interaction of MYC and HDAC2 and support a model in which inhibition of class I HDACs directly targets MYC’s transactivating and transrepressing functions.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa191
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 7
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    Online Resource
    LGG-26. Predicting MAPK inhibitor sensitivity in pediatric low-grade gliomas with novel gene expression-derived signatures
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i93-i94
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i93-i94
    Abstract: Pediatric low-grade glioma (pLGG), the most common brain tumors in children, are driven by alterations in the MAPK pathway. Several clinical trials have shown the potential for MAPK inhibitor (MAPKi) treatment in pLGG. However, the range of response to MAPKi is heterogeneous, even between tumors sharing the same driving MAPK alteration. A predictive stratification tool is needed to identify tumors that will be sensitive to MAPK inhibition. We generated sensitivity gene signatures for each MAPKi class (BRAFi, MEKi, ERKi), based on MAPK-related genes differentially regulated between MAPKi sensitive and non-sensitive cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Single sample Gene Set Enrichment Analysis was used to measure and validate the MAPKi predictive sensitivity scores in the GDSC dataset and an independent patient-derived xenograft (PDX) dataset (XevaDB). The validated signatures were tested in a pLGG-specific background, using gene expression data from pLGG cell lines and primary pLGG samples. Our MAPKi sensitivity signatures discriminated MAPKi sensitive and non-sensitive cells in the GDSC dataset, and significantly correlated with MAPKi response in the PDX dataset. The sensitivity scores discerned gliomas with varying MAPK alterations from those without MAPK alterations, and showed higher scores in pLGG compared to high-grade gliomas and normal brain tissue. MAPKi-predicted sensitivity was heterogeneous within pLGG groups with a common MAPK alteration, as observed in MAPKi clinical trials. Intriguingly, we observed a strong positive correlation between our MAPKi sensitivity signature scores and the predicted immune cell infiltration rate as determined by the ESTIMATE score. These data demonstrate the potential relevance of gene-expression signatures to predict response to MAPKi treatment in pLGG patients, worth of further investigation in a prospective manner in upcoming clinical trials. In addition, our data could support a role of immune cell infiltration in the response to MAPKi in pLGG, warranting further validation.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.340
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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