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  • 1
    In: Neuro-Oncology, 2016, Vol. 18(suppl3), pp.iii110-iii110
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i155-i155
    Description: Identification of multiple distinct subtypes of pediatric brain tumors raises the need for more and better preclinical models reflecting these subtypes. Orthotopic patient-derived xenograft (PDX) models generated by injection of human tumor cells into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Extensive molecular characterization of PDX and matching primary tumor/blood are needed to see how well the PDX represents the original disease, to learn about targetable oncogenic drivers in each model, and to establish or confirm predictive biomarkers. In an ongoing world-wide effort we have generated and fully characterized thus far 130 PDX models reflecting 22 distinct molecular subtypes of pediatric brain tumors. PDX models always retain their molecular subtype as assessed by DNA methylation analysis and in the vast majority of cases also the mutations and copy number alterations when compared to their primary tumors. Most aggressive tumors, such as those having MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines are included. All models and corresponding molecular data will become available for the community for preclinical research. Our repertoire of PDX models and corresponding molecular characterizations allow researchers to find the right models for their specific scientific questions. It provides an unprecedented resource to study tumor biology and paves the way for improving treatment strategies for children with malignant brain tumors.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 3
    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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