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  • 1
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    EXTH-29. RADIOSENSITIZATION BY BRD4 INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii215-vii216
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii215-vii216
    Abstract: Diffuse intrinsic pontine glioma (DIPG), the most frequent brainstem tumor in pediatrics, is one of the devastating childhood cancers, and virtually all patients die within two years after diagnosis. Since these tumors occur in the brainstem which is vital area, there are no surgical options for providing relief to patients, and conventional chemotherapy. Radiation therapy (RT) remains the only effective treatment. Radiosensitization is a mean to improve the therapeutic balance between efficacy and toxicity of RT, but not used in clinically. Here, we found BRD4 inhibitor as a radiosensitizer from drug screening. DIPG shows increased H3 K27 acetylation (H3K27ac), which binds to BET bromodomain protein 4 (BRD4) and they are strongly associated with active transcription. We tested two BRD4 inhibiter (BRD4i : AZD5153 and JQ-1) and genetic BRD4 depletion enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. We evaluated the effects of BRD4i on genes expression using RNA sequence, inhibited significantly DNA-repair proteins such as BRCA1 and RAD51. CUT-RUN qPCR showed decreased H3K27ac at BRCA1 and RAD51. Combination with BRD4i and RT inhibited cell viability significantly in clonogenic survival assay, apoptosis assay, and showed cell cycle arrest. Radiation-induced DNA double-strand break (DSB) repair was prolonged high level of rH2AHX and 53BP1 with BRD4i because of inhibited DNA-repair. In vivo studies revealed increased survival of animals treated with combination therapy of RT and BRD4i in compared to either monotherapy. Together, these results highlight BRD4i as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.828
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 2
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    Design, synthesis and evaluation of novel indole-2-carboxamides for growth inhibition of Mycobacterium tuberculosis and paediatric brain tumour cells
    Royal Society of Chemistry (RSC) ; 2021
    In:  RSC Advances Vol. 11, No. 26 ( 2021), p. 15497-15511
    Details
    In: RSC Advances, Royal Society of Chemistry (RSC), Vol. 11, No. 26 ( 2021), p. 15497-15511
    Type of Medium: Online Resource
    ISSN: 2046-2069
    URL: Article
    DOI: 10.1039/D0RA10728J
    Language: English
    Publisher: Royal Society of Chemistry (RSC)
    Publication Date: 2021
    detail.hit.zdb_id: 2623224-8
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  • 3
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    ATRT-02. THE AURORA KINASE A (AURKA) INHIBITOR ALISERTIB ACTS SYNERGISTICALLY WITH A POLO-LIKE KINASE 4 (PLK4) INHIBITOR TO TARGET ATYPICAL TERATOID / RHABDOID TUMOR (AT/RT) CELLS
    Oxford University Press (OUP) ; 2018
    In:  Neuro-Oncology Vol. 20, No. suppl_2 ( 2018-06-22), p. i27-i27
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_2 ( 2018-06-22), p. i27-i27
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noy059.001
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2094060-9
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  • 4
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    Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)
    MDPI AG ; 2018
    In:  Bioengineering Vol. 5, No. 4 ( 2018-11-04), p. 96-
    Details
    In: Bioengineering, MDPI AG, Vol. 5, No. 4 ( 2018-11-04), p. 96-
    Abstract: Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value 〈 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.
    Type of Medium: Online Resource
    ISSN: 2306-5354
    URL: Article
    DOI: 10.3390/bioengineering5040096
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2746191-9
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  • 5
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    Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets
    American Society for Microbiology ; 2013
    In:  Antimicrobial Agents and Chemotherapy Vol. 57, No. 10 ( 2013-10), p. 4645-4652
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 57, No. 10 ( 2013-10), p. 4645-4652
    Abstract: The Plasmodium falciparum and P. berghei genomes each contain three dipeptidyl aminopeptidase ( dpap ) homologs. dpap1 and -3 are critical for asexual growth, but the role of dpap2 , the gametocyte-specific homolog, has not been tested. If DPAPs are essential for transmission as well as asexual growth, then a DPAP inhibitor could be used for treatment and to block transmission. To directly analyze the role of DPAP2, a dpap2 -minus P. berghei ( Pbdpap2 Δ) line was generated. The Pbdpap2 Δ parasites grew normally, differentiated into gametocytes, and generated sporozoites that were infectious to mice when fed to a mosquito. However, Pbdpap1 transcription was 〉 2-fold upregulated in the Pbdpap2 Δ clonal lines, possibly compensating for the loss of Pbdpap2 . The role of DPAP1 and -3 in the dpap2 Δ parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to the Pbdpap2 Δ parasites just before a mosquito membrane feed, mosquito infectivity was not affected. To assess longer exposures to ML4118S and further evaluate the role of DPAPs during gametocyte development in a parasite that causes human malaria, the dpap2 deletion was repeated in P. falciparum . Viable P. falciparum dpap2 ( Pfdpap2 )-minus parasites were obtained that produced morphologically normal gametocytes. Both wild-type and Pfdpap2 -negative parasites were sensitive to ML4118S, indicating that, unlike many antimalarials, ML4118S has activity against parasites at both the asexual and sexual stages and that DPAP1 and -3 may be targets for a dual-stage drug that can treat patients and block malaria transmission.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02495-12
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2013
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 6
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    EXTH-08. DEVELOPMENT OF NOVEL HISTONE DEMETHYLASE INHIBITOR AGAINST DIPG
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii210-vii210
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii210-vii210
    Abstract: Diffuse intrinsic pontine glioma (DIPG) is one of most the devastating pediatric brain tumors, and virtually all patients die within two years after diagnosis. It has been shown that targeted inhibition of JMJD3 demethylase activity by GSK-J4 results in restored K27 methylation and a significant delay of tumor progression and prolonged animal survival in intracranial DIPG patient-derived xenograft (PDX) models. Because of its promising anti-tumor activities, GSK-J4 has been used to treat many kinds of tumors in preclinical models including leukemia, lymphoma, neuroblastoma, prostate, and gastric cancer, and DIPG; however, GSK-J4 is not yet in clinical development. The major challenge for GSK-J4 in clinical development is that GSK-J4 is a prodrug and is rapidly converted in vivo to the active drug GSK-J1, which has restricted cellular and brain permeability. Hypothesis: We hypothesize that development of a stable GSK- J1 analog that offers good cellular and brain transport is essential to improving in vivo efficacy and is required for clinical application of this class of compounds. METHODS We developed a novel alcohol derivative of GSK-J1, UR-8, as a lead anti-cancer agent through our screening and drug development activities. RESULTS UR-8 has demonstrated selective cytotoxic activity against human K27M DIPG cells in vitro and apparently transported the brain to a useful extent based on its in vivo bio-distribution and effectiveness. CONCLUSION UR-8 showed greater anti-tumor activity and survival benefit than that obtained by GSK-J4 treatment in intracranial DIPG PDX models.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.807
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 7
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    EXTH-82. THERAPEUTIC TARGETING OF EZH2 AND BET BRD4 IN PEDIATRIC RHABDOID TUMORS
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii228-vii228
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii228-vii228
    Abstract: Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. Thus, targeting distinct histone modifier activities would be an effective approach for treating AT/RT. METHODS The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. RESULTS AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. Genes associated with DNA-repair pathway was downregulated upon EZH2 and BRD4 inhibition, and the sensitivity to cisplatin was elevated upon combination of EZH2 and BRD4 inhibitors in vitro. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. CONCLUSION Histone H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is therefore a potential combination therapy for AT/RT.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.880
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 8
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    Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer
    MDPI AG ; 2019
    In:  International Journal of Molecular Sciences Vol. 20, No. 9 ( 2019-04-29), p. 2112-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 20, No. 9 ( 2019-04-29), p. 2112-
    Abstract: Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms20092112
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 9
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    Sex- and stage-specific reporter gene expression in Plasmodium falciparum
    Elsevier BV ; 2008
    In:  Molecular and Biochemical Parasitology Vol. 160, No. 2 ( 2008-08), p. 148-151
    Details
    In: Molecular and Biochemical Parasitology, Elsevier BV, Vol. 160, No. 2 ( 2008-08), p. 148-151
    Type of Medium: Online Resource
    ISSN: 0166-6851
    URL: Article
    DOI: 10.1016/j.molbiopara.2008.04.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 1491098-6
    SSG: 12
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  • 10
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    Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Communications Vol. 10, No. 1 ( 2022-10-23)
    Details
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2022-10-23)
    Abstract: Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    URL: Article
    DOI: 10.1186/s40478-022-01463-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2715589-4
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