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Berlin Brandenburg

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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i131-i131
    Description: Medulloblastoma is the most common malignant pediatric brain tumor and comprises at least four distinct biological subgroups. MYC-driven tumorigenesis constitutes a hallmark feature underlying Group 3 biology and metastatic dissemination at diagnosis or recurrence constitutes a major clinical problem in this highly aggressive subgroup. Employing our institutional drug screening platform, we evaluated an in-house library of over 200 histone deacetylase inhibitors (HDACi) in various brain tumor cell lines and patient-derived primary cultures including glioblastoma (n=8), medulloblastoma (n=10) and atypical teratoid/rhabdoid tumors (n=11). Thereby, we identified CI-994, a clinically established class I specific HDAC inhibitor, which selectively inhibited proliferation of MYC-driven medulloblastoma in our primary and secondary screen. We confirmed the MYC-dependent response in medulloblastoma cell lines with CRISPR/CAS9-based MYC overexpression compared to their isogenic controls with low MYC expression. Notably, inhibitor treatment resulted in significantly reduced MYC mRNA and protein expression levels, decreased cell viability and induction of apoptosis. Additionally, a screen for synergism with a clinical inhibitor library (clinical phase III/IV and approved chemotherapeutics) revealed favorable interaction with NFκB inhibition. Furthermore, integrated proteogenomics using RNA sequencing and proteomic profiling corroborated NFκB pathway activation upon CI-994 treatment. Finally, we demonstrated a significantly prolonged survival, a decrease in tumor growth and spinal metastasis in two orthotopic xenograft mouse models of MYC-driven medulloblastoma. In conclusion, our results suggest a MYC-dependent response to class I HDAC inhibition in medulloblastoma and provide compelling rationale for further development of a novel, potentially highly effective therapeutic strategy against the primary site and, importantly, the metastatic compartment.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i112-i112
    Description: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA formation. While five-year overall survival rates exceed 95%, incompletely resected tumors recur frequently despite treatment. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach utilizes RNA sequencing and LC/MS-based proteomic profiling and Similarity Fusion Network (SNF) analysis reveals the biological heterogeneity of PA. Integrative genomics dissects aberrant pathway activation in biological subgroups. Lastly, we utilize a drug screening pipeline to evaluate selective therapeutic activity of conventional anti-cancer and phase III/IV clinical trial drugs in PA culture models. PAs segregate into three groups with distinct clinical and molecular features. Age and tumor location are significantly associated with the SNF groups. BRAF fusions were predominantly observed in Groups 1 and 2, while Group 3 PA largely harbored other alterations leading to MAPK activation. Pathway enrichment analyses reveals genesets involved in primary ciliogenesis in Group 3, while immune response signatures, many SYK-related, are associated with Group 1. Confirming this analysis, the SYK inhibitor R788 was specifically active in Group 1, and less active in other brain tumors models (n=27). In summary, our proteogenomic approach reveals important biological heterogeneity with novel therapeutic targets emerging in PA. These biological insights may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of progressive disease.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 3
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i80-i80
    Description: Ependymoma is the third most common brain tumor in children. Subsets of ependymomas, in particular RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, are associated with frequent recurrence and dismal outcome. Neurosurgical resection and radiotherapy are the main therapeutic options, while response to conventional chemotherapy is limited. We aimed to establish a high-throughput drug screening (HTS) pipeline for comprehensive individualized testing of patient-derived primary cultures to identify novel therapeutic targets for ependymomas. Ependymoma primary cultures (n=6) were established following tumor resection and underwent HTS in 1536-well plates to allow large-scale drug screening despite limited cell numbers. We generated dose-response data with 9 dilution steps (dose range 32.5nM to 25µM) for a clinical inhibitor library (n=196) comprising established chemotherapeutic agents and novel anti-cancer compounds currently in phase III and IV studies. The Infinium MethylationEPIC Array was used to characterize primary tumors and matched primary cultures genomically and epigenetically. DNA methylation and copy number profiles revealed that short-term primary cultures faithfully recapitulate the genomic and epigenetic landscape of the corresponding primary tumors. Comparison of drug response data from ependymomas, other pediatric brain tumors (n=25) and controls (i.e. non-neoplastic neural progenitor cells) confirmed extraordinary chemoresistance of ependymomas but also revealed promising selectively active drugs, such as neratinib, an irreversible ERBB2 inhibitor. Thus, our data demonstrate the feasibility of HTS in primary cultures derived from pediatric brain tumors and provide preclinical evidence suggesting inhibition of ERBB2 as a promising therapeutic option in a subset of otherwise highly chemoresistant ependymomas.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 4
    Language: English
    In: Oncotarget, 14 February 2017, Vol.8(7), pp.11460-11479
    Description: Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:BRAF fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ-BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40-TAg inhibits TP53/CDKN1A and CDKN2A/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549:BRAF fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, CDKN2A (p16), CDKN1A (p21), and TP53 (p53) protein, and gene-expression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by TERT expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while BRAF V600E- and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient-derived long term expandable PA cell line expressing the KIAA1549:BRAF-fusion suitable for preclinical drug testing.
    Keywords: Kiaa1549:Braf-Fusion ; Mapk-Inhibitors ; Oncogene-Induced Senescence (Ois) ; Pediatric Low Grade Glioma ; Pilocytic Astrocytoma ; Astrocytoma ; Brain Neoplasms ; Cell Culture Techniques ; Cell Line, Tumor ; Cellular Senescence -- Physiology
    E-ISSN: 1949-2553
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  • 5
    In: International Journal of Cancer, 15 December 2019, Vol.145(12), pp.3402-3413
    Description: Medulloblastoma is the most common malignant brain cancer in children. Since previous studies have mainly focused on alterations in the coding genome, our understanding of the contribution of long noncoding RNAs (lncRNAs) to medulloblastoma biology is just emerging. Using patient‐derived data, we show that the promoter of lncRNA is hypomethylated and that the transcript is highly expressed in the SHH subgroup. Furthermore, high expression of is correlated with poor outcome in patients with TP53 wild‐type SHH tumors. Silencing in medulloblastoma tumor cells induced apoptosis, while proliferation and migration were inhibited in culture. , silencing in medulloblastoma tumor cells resulted in reduced tumor growth, reduced proliferation of tumor cells, increased apoptosis and led to prolonged survival of tumor‐bearing mice. Together, our study suggests that the lncRNA is a prognostic marker and therapeutic target in medulloblastoma tumors and serves as a proof of concept that lncRNAs are important factors in the disease. What's new? Long non‐coding RNAs (lncRNAs) influence diverse cellular activities, including gene expression and the activity of adjacent genes. Hence, some lncRNAs are implicated in cancer. Here, the lncRNA was investigated for a possible functional role in medulloblastoma. was found to be overexpressed in medulloblastoma cells, with expression levels correlated to hypomethylation. Functionally, prevented cell death and promoted proliferation and tumorigenicity of medulloblastoma tumor cells and . Mice injected with knockdown medulloblastoma tumor cells exhibited reduced tumor growth and improved survival. The findings identify as a potential marker and therapeutic target in medulloblastoma.
    Keywords: Gene Regulation ; Sonic Hedgehog ; Oncogene
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 6
    Language: English
    In: Pediatric Blood & Cancer, 2019, Vol.66(6), p.n/a(4)
    Description: Byline: Liana Nobre, David Pauck, Brian Golbourn, Mara Maue, Eric Bouffet, Marc Remke,Vijay Ramaswamy Keywords: medulloblastoma; neuropathy; subgroup; vinblastine Abstract Most medulloblastoma protocols worldwide include vincristine during radiation and chemotherapy. A significant dose-limiting toxicity is peripheral neuropathy; however, there is a paucity of data to support the view that omission of vincristine does not impact survival. Herein we report two adolescent patients with Group 4 and SHH medulloblastoma, where vinblastine successfully replaced vincristine with resolution of their peripheral neuropathy. We furthermore show vinblastine is highly active in vitro and demonstrates equivalent antitumoral activity compared to vincristine. Substitution of vincristine with vinblastine in future studies should be considered for all patients with medulloblastoma, particularly those with hereditary neuropathy, severe vincristine toxicity, and adults. Article Note: Liana Nobre and David Pauck are shared first authors. Marc Remke and Vijay Ramaswamy are shared senior authors. CAPTION(S): Supplemental Table 1. In vitro models used for screening of vinblastine and vincristine activity
    Keywords: Medulloblastoma – Analysis ; Vincristine – Usage ; Vincristine – Analysis ; Tumors – Analysis ; Medical Research – Analysis ; Chemotherapy – Analysis
    ISSN: 1545-5009
    E-ISSN: 15455017
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  • 7
    In: Pediatric Blood & Cancer, June 2019, Vol.66(6), pp.n/a-n/a
    Description: Most medulloblastoma protocols worldwide include vincristine during radiation and chemotherapy. A significant dose‐limiting toxicity is peripheral neuropathy; however, there is a paucity of data to support the view that omission of vincristine does not impact survival. Herein we report two adolescent patients with Group 4 and SHH medulloblastoma, where vinblastine successfully replaced vincristine with resolution of their peripheral neuropathy. We furthermore show vinblastine is highly active in vitro and demonstrates equivalent antitumoral activity compared to vincristine. Substitution of vincristine with vinblastine in future studies should be considered for all patients with medulloblastoma, particularly those with hereditary neuropathy, severe vincristine toxicity, and adults.
    Keywords: Medulloblastoma ; Neuropathy ; Subgroup ; Vinblastine
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: John Wiley & Sons, Inc.
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  • 8
    Language: English
    In: Neuro-Oncology, 04/23/2019, Vol.21(Supplement_2), pp.ii100-ii100
    Description: Abstract Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA tumorigenesis. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely...
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
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  • 9
    Language: English
    In: Neuro-Oncology, 04/23/2019, Vol.21(Supplement_2), pp.ii107-ii107
    Description: Abstract Medulloblastoma is the most common malignant brain tumor in childhood and comprises four distinct molecular subgroups with further layers of intertumoral heterogeneity. Amplification of the oncogene MYC drives tumorigenesis and constitutes a hallmark feature underlying Group...
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
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  • 10
    Language: English
    In: Neuro-Oncology, 04/23/2019, Vol.21(Supplement_2), pp.ii78-ii79
    Description: Abstract Ependymoma represents the third most common brain tumor entity of childhood. Successful targeted treatment approaches especially for RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, the two subgroups known to be associated with worst prognosis,...
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
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