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  • Wechsler-Reya, Robert  (9)
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  • 1
    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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  • 2
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 17 December 2018
    Description: Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anti-cancer small molecule in clinical trials for high grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that opposes DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201. The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in 〉1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. Immunohistochemistry staining of DRD2/DRD5 was performed in tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies. DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from recurrent glioblastoma patients treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes. These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 3
  • 4
    Language: English
    In: Science signaling, 11 September 2018, Vol.11(547)
    Description: A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.
    Keywords: Signal Transduction ; Casein Kinase II -- Metabolism ; Cerebellar Neoplasms -- Metabolism ; Hedgehog Proteins -- Metabolism ; Medulloblastoma -- Metabolism ; Phosphoproteins -- Metabolism ; Proteomics -- Methods
    ISSN: 19450877
    E-ISSN: 1937-9145
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  • 5
    Language: English
    In: Nature Communications, 01 January 2019, Vol.10(1), pp.1-13
    Description: Medulloblastoma is one of the most prevalent malignant brain tumors in children and has very poor prognosis. In this study, the authors show, using a mouse model of medulloblastoma, that Gfi1 promotes tumor growth by recruiting Lsd1, that this interaction inhibits genes involved in neuronal differentiation, and that Lsd1 may be a therapeutic target in Gfi1-activated tumors.
    Keywords: Biology
    E-ISSN: 2041-1723
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  • 6
    Language: English
    In: Nature, August 2019, Vol.572(7767), pp.74-79
    Description: Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored....
    Keywords: Genomics ; Single-Cell Analysis ; Transcriptome ; Medulloblastoma -- Genetics
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 7
    In: Nature, 2017
    Description: Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 8
    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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  • 9
    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)
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