Kooperativer Bibliotheksverbund

Berlin Brandenburg

and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Type of Medium
Language
Year
  • 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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: Journal of medicinal chemistry, 13 July 2017, Vol.60(13), pp.5334-5348
    Description: The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC values in the low μM and sub-μM range. 1g-i revealed low nM IC values for HDAC6 with up to 15-fold preference over HDAC1, 〉3500-fold selectivity over HDAC4, and 〉100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.
    Keywords: Antineoplastic Agents -- Pharmacology ; Cisplatin -- Pharmacology ; Histone Deacetylase Inhibitors -- Pharmacology ; Histone Deacetylases -- Metabolism ; Urea -- Pharmacology
    ISSN: 00222623
    E-ISSN: 1520-4804
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    Language: English
    In: Blood, 19 July 2018, Vol.132(3), pp.307-320
    Description: Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34CD38) as well as the leukemic bulk (CD34CD38) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.
    Keywords: Animals–Chemistry ; Antineoplastic Agents–Pharmacology ; Binding Sites–Drug Effects ; Biomarkers, Tumor–Drug Effects ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Antagonists & Inhibitors ; Cell Survival–Chemistry ; Disease Models, Animal–Antagonists & Inhibitors ; Drug Resistance, Neoplasm–Chemistry ; Fusion Proteins, Bcr-Abl–Metabolism ; Hsp90 Heat-Shock Proteins–Drug Effects ; Heat-Shock Response–Chemistry ; Humans–Pharmacology ; Imatinib Mesylate–Drug Therapy ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive–Metabolism ; Mice–Chemistry ; Models, Molecular–Pharmacology ; Molecular Conformation–Drug Effects ; Molecular Structure–Drug Effects ; Protein Binding–Drug Effects ; Protein Interaction Domains and Motifs–Drug Effects ; Protein Kinase Inhibitors–Drug Effects ; Protein Multimerization–Drug Effects ; Spectrum Analysis–Drug Effects ; Structure-Activity Relationship–Drug Effects ; Xenograft Model Antitumor Assays–Drug Effects ; Abridged ; Antineoplastic Agents ; Biomarkers, Tumor ; Hsp90 Heat-Shock Proteins ; Protein Kinase Inhibitors ; Imatinib Mesylate ; Fusion Proteins, Bcr-Abl;
    ISSN: 00064971
    E-ISSN: 1528-0020
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: European Journal of Medicinal Chemistry, 05 May 2015, Vol.95, pp.249-266
    Description: Targeting TGFβ/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of -annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, through induction of TGFβ receptor type II degradation. In the present work, 〉40 rationally designed, novel DHPs were synthesized and evaluated for TGFβ inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4″-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are ( )-configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r  = 0.93) with a good predictive power (r  = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGFβ inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands ( , lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies .
    Keywords: Transforming Growth Factor Β (Tgfβ) ; Structure–Activity Relationships (Sars) ; B-Anellated 1,4-Dihydropyridines (1,4-Dhps) ; Absolute Configuration ; Crystal Structure ; Molecular Electrostatic Potential (MEP) ; 3d-Qsar Model ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0223-5234
    E-ISSN: 1768-3254
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
  • 8
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    Language: English
    Description: An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures....
    Keywords: Crystal Structure ; Experimental 3d Coordinates ; Crystal System ; Space Group ; Cell Parameters ; Crystallography ; Ethyl 4-(Biphenyl-4-Yl)-2,7,7-Trimethyl-5-Oxo-1,4,5,6,7,8-Hexahydroquinoline-3-Carboxylate
    Source: DataCite
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages