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  • Oxford University Press (CrossRef)  (7)
  • 1
    In: Neuro-Oncology, 2015, Vol. 17(suppl3), pp.iii33-iii33
    Description: Brain tumors are the leading cause of cancer-related mortality in childhood. Based on the many recent genomic studies, we know now that multiple molecular subtypes of brain cancers exist that are not only biologically but also clinically highly distinct. These findings may lead to novel treatment strategies. For this we need better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NOD scid gamma (NSG) mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations are needed to learn about targetable oncogenic drivers in each model. Therefore, we aim to generate a large repertoire of PDX models reflecting the many different molecular subtypes of pediatric brain cancer. For each established PDX model, we perform DNA methylation profiling, gene expression profiling, low-coverage whole genome sequencing and whole exome sequencing and compare these data with the matching primary tumor. Thus far, as a collaborative effort between different laboratories, we have established and fully characterized 34 PDX models from 1 atypical teratoid rhabdoid tumor (ATRT), 4 ependymoma, 9 glioblastoma, 18 medulloblastoma, and 2 primitive neuroectodermal tumors (PNET). Molecular analysis of all available PDX models identified a clear overrepresentation of most aggressive tumors such as models characterized by MYC- or MYCN amplification. Other, less aggressive cancers, like Wnt medulloblastoma, are underrepresented. For in vivo imaging during treatment of PDX models we created luciferase labeled PDX sublines. Our data demonstrate that PDX models retain characteristics of the primary human tumors from which they were derived. These reagents provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies of malignant pediatric brain tumors.
    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
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i142-i142
    Description: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Even with an intensive therapeutic regimen of surgery, radiation and chemotherapy, one-third of patients still succumb to their disease and survivors suffer devastating side effects from the therapy. Thus, more effective and less toxic therapies are desperately needed. Genomic analyses have identified four major subgroups of MB – WNT, SHH, Group 3 and Group 4 – that differ in terms of mutations, gene expression and patient outcomes. Despite this heterogeneity, all MB patients currently receive similar therapies. To identify novel therapies for each subgroup of MB, we have assembled a panel of patient-derived xenograft (PDX) lines established by orthotopic transplantation of tumor cells obtained from surgery. We used these PDXs to perform high-throughput drug screening, and integrated drug response data with mutational, transcriptional, and epigenetic profiles. These studies revealed significant heterogeneity in drug responses among MB patients, and identified the RNA synthesis inhibitor Actinomycin D as a potent inhibitor of Group 3 MB, the most aggressive form of the disease. Based on these studies, we hope to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are likely to be more effective against their tumor.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 4
  • 5
    Language: English
    In: Neuro-Oncology, 04/23/2019, Vol.21(Supplement_2), pp.ii93-ii93
    Description: Abstract Many immunotherapies act by enhancing the ability of T cells to kill tumor cells. But T cell killing depends on recognition of antigens presented by Class I MHC (MHC-I) on the tumor cell surface; if a tumor lacks MHC-I, it cannot be recognized by T cells. To study the efficacy...
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
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  • 6
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi276-vi276
    Description: Tumor recurrence is the main cause of death among children with medulloblastoma, the most frequent type of malignant pediatric brain tumors. The medulloblastoma subgroup Group 3 has the poorest survival of all four subgroups, and is associated with a high rate of tumor recurrence in children. Mechanisms behind medulloblastoma recurrence are not yet well understood. We found that the transcription factor SOX9 marks quiescent brain tumor stem cells and is suppressed by MYC overexpression in aggressive Group 3 tumors. By using our inducible Tet-OFF transgenic (GTML) mouse model for malignant MYCN-driven Group 3 tumors and human Group 3 MYC-driven patient-derived xenograft (PDX) models we identified rare SOX9-positive, slow-cycling brain tumor cells that are more resistant to standard chemotherapy. Dox treatment normally cures GTML transgenic animals that developed aggressive medulloblastoma by turning MYCN off. However, when crossing the Tet-OFF GTML model with a Tet-ON rtTA-Sox9 model we can redirect MYCN expression to the control of the Sox9 promoter - ultimately driving brain tumor recurrence from rare SOX9-positive cells with 100% penetrance. These recurrent tumors were actively disseminating from the hindbrain into the forebrain. Expression profiling shows that recurring tumors have increased levels of SOX9, are more inflammatory and have elevated levels of MGMT methyltransferase, compared to the primary tumors. Overexpressing SOX9 into Group 3 MB cells directly inhibited MYC, and decreased cell proliferation while promoting metastasis. Paired primary and recurrent human Group 3 and Group 4 tumor biopsies also showed significantly higher levels of SOX9 at recurrence. PDX models of Group 3 tumors further showed increased levels of SOX9 positivity in metastatic compartments. Our data unveils complex mechanisms by which dormant medulloblastoma cells fail to respond to standard therapy and generate tumor relapses.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 7
    Language: English
    In: Neuro-Oncology, 11/01/2016, 11/01/2016, Vol.18(suppl_6), pp.vi154-vi155
    Description: Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an intensive regimen of surgery, radiation and chemotherapy, one-third of patients still die from their disease, and survivors suffer devastating side effects from the therapy. Thus, more effective and less toxic therapies are desperately needed. Genomic analyses have identified 4 major subgroups of MB – WNT, SHH, Group 3 and Group 4 – that differ in terms of mutations, gene expression and patient outcomes. Despite this heterogeneity, all MB patients currently receive the same therapy. To identify novel therapies for each subgroup of MB, we have assembled a panel of patient-derived xenograft (PDX) lines. These lines, established by orthotopic transplantation of tumor cells obtained from surgery, recapitulate the properties of patients’ tumors more accurately than cultured cell lines. We are using these lines to screen small molecule libraries for compounds that can inhibit tumor growth and survival. To date we have completed 19 lines, including 10 representing Group 3, the most aggressive and lethal form of the disease. Among ~7800 compounds tested, 22 were effective against all Group 3 lines. Ongoing studies are focused on validating the activity of these compounds and moving the most promising ones forward into in vivo efficacy studies. Similar approaches will be pursued for each of the other subgroups of MB. Drug response data will also be compared with genomic and epigenomic data (whole exome and low coverage whole genome DNA sequencing, DNA methylation analysis, and gene expression profiling) to identify biomarkers of drug responsiveness and key pathways that may be exploited for therapy. Based on these studies, we hope to move away from a one-size-fits-all approach, and begin to treat each patient with therapies that are likely to be effective against their tumor.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    Source: Oxford University Press (via CrossRef)
    Library Location Call Number Volume/Issue/Year Availability
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