28 results on '"Marquardt V"'
Search Results
2. CBF1 is clinically prognostic and serves as a target to block cellular invasion and chemoresistance of EMT-like glioblastoma cells.
- Author
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Maciaczyk, D, Picard, D, Zhao, L, Koch, K, Herrera-Rios, D, Li, G, Marquardt, V, Pauck, D, Hoerbelt, T, Zhang, W, Ouwens, D M, Remke, M, Jiang, T, Steiger, H J, Maciaczyk, J, and Kahlert, U D
- Subjects
ANTINEOPLASTIC agents ,PROTEIN metabolism ,RNA metabolism ,BRAIN tumors ,CANCER invasiveness ,CELL lines ,CELL physiology ,COMPUTER simulation ,DATABASES ,DRUG resistance in cancer cells ,GLIOMAS ,GLYCOLYSIS ,GENETIC mutation ,OXIDOREDUCTASES ,PROGNOSIS ,PROTEINS ,STEM cells ,WESTERN immunoblotting ,DACARBAZINE ,THERAPEUTICS - Abstract
Background: Glioblastoma is the most common and most lethal primary brain cancer. CBF1 (also known as Recombination signal Binding Protein for immunoglobulin kappa J, RBPJ) is the cardinal transcriptional regulator of the Notch signalling network and has been shown to promote cancer stem-like cells (CSCs) in glioblastoma. Recent studies suggest that some of the malignant properties of CSCs are mediated through the activation of pro-invasive programme of epithelial-to-mesenchymal transition (EMT). Little is known whether CBF1 is involved in the EMT-like phenotype of glioma cells.Methods: In a collection of GBM neurosphere lines, we genetically inhibited CBF1 and investigated the consequences on EMT-related properties, including in vitro invasiveness by Boyden chambers assay, chemoresistance using a clinical drug library screen and glycolytic metabolism assessing live-cell extracellular acidification rate. We also compared CBF1 expression in cells exposed to low and high oxygen tension. In silico analysis in large-scale Western and Eastern patient cohorts investigated the clinical prognostic value of CBF1 expression in low- and high-grade glioma as well as medulloblastoma.Results: Mean CBF1 expression is significantly increased in isocitrate dehydrogenase 1 (IDH1) R132H mutant glioblastoma and serves as prognostic marker for prolonged overall survival in brain tumours, particularly after therapy with temozolomide. Hypoxic regions of glioblastoma have higher CBF1 activation and exposure to low oxygen can induce its expression in glioma cells in vitro. CBF1 inhibition blocks EMT activators such as zinc finger E-box-binding homeobox 1 (ZEB1) and significantly reduces cellular invasion and resistance to clinically approved anticancer drugs. Moreover, we indicate that CBF1 inhibition can impede cellular glycolysis.Conclusions: Mean CBF1 activation in bulk tumour samples serves as a clinical predictive biomarker in brain cancers but its intratumoral and intertumoral expression is highly heterogeneous. Microenvironmental changes such as hypoxia can stimulate the activation of CBF1 in glioblastoma. CBF1 blockade can suppress glioblastoma invasion in vitro in particular in cells undergone EMT such as those found in the hypoxic niche. Targeting CBF1 can be an effective anti-EMT therapy to impede invasive properties and chemosensitivity in those cells. [ABSTRACT FROM AUTHOR]- Published
- 2017
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3. Synthesis of tritium labelled 24-epibrassinolide.
- Author
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Kolbe, A., Marquardt, V., and Adam, G.
- Published
- 1992
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4. ChemInform Abstract: Aspects of Synthesis and Bioactivity of Brassinosteroids.
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ADAM, G., MARQUARDT, V., VORBRODT, H. M., HOERHOLD, C., ANDREAS, W., and GARTZ, J.
- Published
- 1993
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5. Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation.
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Marquardt V, Theruvath J, Pauck D, Picard D, Qin N, Blümel L, Maue M, Bartl J, Ahmadov U, Langini M, Meyer FD, Cole A, Cruz-Cruz J, Graef CM, Wölfl M, Milde T, Witt O, Erdreich-Epstein A, Leprivier G, Kahlert U, Stefanski A, Stühler K, Keir ST, Bigner DD, Hauer J, Beez T, Knobbe-Thomsen CB, Fischer U, Felsberg J, Hansen FK, Vibhakar R, Venkatraman S, Cheshier SH, Reifenberger G, Borkhardt A, Kurz T, Remke M, and Mitra S
- Subjects
- Humans, Mice, Animals, NF-kappa B metabolism, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use, Protein Glutamine gamma Glutamyltransferase 2, Quality of Life, Phagocytosis, Macrophages, Inflammation metabolism, Medulloblastoma drug therapy, Glioblastoma, Cerebellar Neoplasms
- Abstract
Background: While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway., Methods: We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models., Results: CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice., Conclusion: Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses., Competing Interests: Competing interests: SHC and SSM hold a Patent entitled ‘Treatment of pediatric brain tumors with targeting of CD47 pathway’. Other authors hold no potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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6. Grace Notes: feasibility of a manualized intervention to advance spiritual well-being for clients with acquired brain injury.
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Thompson M, Rabusch S, Radomski MV, Marquardt V, Kath K, Kreiger R, and Squires K
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- Adult, Feasibility Studies, Humans, Brain Injuries psychology, Brain Injuries rehabilitation, Spirituality
- Abstract
Spiritual well-being appears to contribute to mental health and adaptation in adults with acquired brain injury (ABI). ABI-related interventions, including those associated with spirituality, must be specifically designed with learning-related impairments in mind. We conducted a feasibility study of a manualized intervention to support spiritual well-being after ABI called Grace Notes. The goal is to provide clients with time tested, easily accessible spiritual practices that help them experience deeper feelings of being in relationship with their Higher Power as they understand it. Findings suggest that Grace Notes can be implemented by both its developer with the context of an interdisciplinary outpatient rehabilitation program and a rehabilitation clinician as a stand-alone group. People with ABI appear to be interested in a spiritually intervention that draws from a variety of spiritual practices and traditions. Further study related to the efficacy of spiritual well-being intervention after ABI is warranted.
- Published
- 2022
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7. The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors.
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Bartl J, Zanini M, Bernardi F, Forget A, Blümel L, Talbot J, Picard D, Qin N, Cancila G, Gao Q, Nath S, Koumba IM, Wolter M, Kuonen F, Langini M, Beez T, Munoz C, Pauck D, Marquardt V, Yu H, Souphron J, Korsch M, Mölders C, Berger D, Göbbels S, Meyer FD, Scheffler B, Rotblat B, Diederichs S, Ramaswamy V, Suzuki H, Oro A, Stühler K, Stefanski A, Fischer U, Leprivier G, Willbold D, Steger G, Buell A, Kool M, Lichter P, Pfister SM, Northcott PA, Taylor MD, Borkhardt A, Reifenberger G, Ayrault O, and Remke M
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- Animals, Carrier Proteins metabolism, Cell Line, Tumor, Cell Proliferation, Dyneins metabolism, Gene Expression Regulation, Neoplastic, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Humans, Membrane Glycoproteins metabolism, Mice, Cerebellar Neoplasms genetics, Medulloblastoma genetics, MicroRNAs genetics, RNA, Long Noncoding genetics
- Abstract
Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors., (© 2022. The Author(s).)
- Published
- 2022
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8. The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma.
- Author
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Ahmadov U, Picard D, Bartl J, Silginer M, Trajkovic-Arsic M, Qin N, Blümel L, Wolter M, Lim JKM, Pauck D, Winkelkotte AM, Melcher M, Langini M, Marquardt V, Sander F, Stefanski A, Steltgens S, Hassiepen C, Kaufhold A, Meyer FD, Seibt A, Kleinesudeik L, Hain A, Münk C, Knobbe-Thomsen CB, Schramm A, Fischer U, Leprivier G, Stühler K, Fulda S, Siveke JT, Distelmaier F, Borkhardt A, Weller M, Roth P, Reifenberger G, and Remke M
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis pathology, Cell Line, Tumor, Cell Survival genetics, Clone Cells, Down-Regulation genetics, Gene Expression Regulation, Neoplastic, Glioblastoma pathology, Humans, Mice, Nude, MicroRNAs genetics, Mitochondria metabolism, Neoplasm Invasiveness, Phenotype, Prognosis, Protein Glutamine gamma Glutamyltransferase 2 metabolism, Proteogenomics, RNA, Small Interfering metabolism, Reactive Oxygen Species metabolism, Mice, Glioblastoma genetics, Glioblastoma radiotherapy, MicroRNAs metabolism, Radiation Tolerance genetics
- Abstract
Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach., (© 2021. The Author(s).)
- Published
- 2021
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9. A Cell-Based MAPK Reporter Assay Reveals Synergistic MAPK Pathway Activity Suppression by MAPK Inhibitor Combination in BRAF -Driven Pediatric Low-Grade Glioma Cells.
- Author
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Usta D, Sigaud R, Buhl JL, Selt F, Marquardt V, Pauck D, Jansen J, Pusch S, Ecker J, Hielscher T, Vollmer J, Sommerkamp AC, Rubner T, Hargrave D, van Tilburg CM, Pfister SM, Jones DTW, Remke M, Brummer T, Witt O, and Milde T
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- Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Proliferation, Child, Glioma drug therapy, Glioma genetics, Glioma metabolism, Humans, Mitogen-Activated Protein Kinases antagonists & inhibitors, Mitogen-Activated Protein Kinases metabolism, Neoplasm Grading, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic drug effects, Genes, Reporter, Glioma pathology, Mitogen-Activated Protein Kinases analysis, Mutation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics
- Abstract
Pilocytic astrocytomas as well as other pediatric low-grade gliomas (pLGG) exhibit genetic events leading to aberrant activation of the MAPK pathway. The most common alterations are KIAA1549:BRAF fusions and BRAF
V600E and NF1 mutations. Novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for the treatment of these single-pathway diseases. We aimed to develop an assay suitable for preclinical testing of MAPKi in pLGGs with the goal to identify novel MAPK pathway-suppressing synergistic drug combinations. A reporter plasmid (pDIPZ) with a MAPK-responsive ELK-1-binding element driving the expression of destabilized firefly luciferase was generated and packaged using a lentiviral vector system. Pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively, were stably transfected. Modulation of the MAPK pathway activity by MAPKi was measured using the luciferase reporter and validated by detection of phosphorylated protein levels. A screening of a MAPKi library was performed, and synergy of selected combinations was calculated. Screening of a MAPKi library revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50 s, followed by ERK and next-generation RAF inhibitors. Combination treatments with different MAPKi classes showed synergistic effects in BRAF fusion as well as BRAFV600E mutation backgrounds. Here, we report a novel reporter assay for medium- to high-throughput preclinical drug testing in pLGG cell lines. The assay confirmed MEK, ERK, and next-generation RAF inhibitors as potential treatment approaches for KIAA1549:BRAF and BRAFV600E -mutated pLGGs. In addition, the assay revealed that combination treatments synergistically suppressed MAPK pathway activity., (©2020 American Association for Cancer Research.)- Published
- 2020
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10. N-Myc-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma.
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Tjaden B, Baum K, Marquardt V, Simon M, Trajkovic-Arsic M, Kouril T, Siebers B, Lisec J, Siveke JT, Schulte JH, Benary U, Remke M, Wolf J, and Schramm A
- Subjects
- Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glucosamine metabolism, Glucose metabolism, Humans, Neuroblastoma genetics, Neuroblastoma metabolism, Neuroblastoma therapy, N-Myc Proto-Oncogene Protein physiology, Neuroblastoma pathology
- Abstract
N-Myc is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of Myc family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of Myc proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of N-Myc overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of N-Myc induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of N-Myc. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of N-Myc overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered N-Myc induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.
- Published
- 2020
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11. Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity.
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Reßing N, Marquardt V, Gertzen CGW, Schöler A, Schramm A, Kurz T, Gohlke H, Aigner A, Remke M, and Hansen FK
- Abstract
Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound 6i , displayed submicromolar tumor cell-inhibitory potential (IC
50 : 0.21-0.67 μM) against all five cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.- Published
- 2018
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12. Targeting HSP90 dimerization via the C terminus is effective in imatinib-resistant CML and lacks the heat shock response.
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Bhatia S, Diedrich D, Frieg B, Ahlert H, Stein S, Bopp B, Lang F, Zang T, Kröger T, Ernst T, Kögler G, Krieg A, Lüdeke S, Kunkel H, Rodrigues Moita AJ, Kassack MU, Marquardt V, Opitz FV, Oldenburg M, Remke M, Babor F, Grez M, Hochhaus A, Borkhardt A, Groth G, Nagel-Steger L, Jose J, Kurz T, Gohlke H, Hansen FK, and Hauer J
- Subjects
- Animals, Antineoplastic Agents chemistry, Binding Sites, Biomarkers, Tumor, Cell Cycle drug effects, Cell Line, Tumor, Cell Survival drug effects, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Fusion Proteins, bcr-abl antagonists & inhibitors, Fusion Proteins, bcr-abl chemistry, HSP90 Heat-Shock Proteins metabolism, Humans, Imatinib Mesylate chemistry, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Mice, Models, Molecular, Molecular Conformation, Molecular Structure, Protein Binding, Protein Kinase Inhibitors chemistry, Spectrum Analysis, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, HSP90 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins chemistry, Heat-Shock Response drug effects, Imatinib Mesylate pharmacology, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors pharmacology, Protein Multimerization drug effects
- Abstract
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 (CD34
+ CD38- ) as well as the leukemic bulk (CD34+ CD38+ ) 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., (© 2018 by The American Society of Hematology.)- Published
- 2018
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13. Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines.
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Stenzel K, Hamacher A, Hansen FK, Gertzen CGW, Senger J, Marquardt V, Marek L, Marek M, Romier C, Remke M, Jung M, Gohlke H, Kassack MU, and Kurz T
- Subjects
- Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cisplatin chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Histone Deacetylase Inhibitors chemical synthesis, Histone Deacetylase Inhibitors chemistry, Humans, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Urea analogs & derivatives, Urea chemistry, Antineoplastic Agents pharmacology, Cisplatin pharmacology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Urea pharmacology
- Abstract
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
50 values in the low μM and sub-μM range. 1g-i revealed low nM IC50 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.- Published
- 2017
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14. Establishment and application of a novel patient-derived KIAA1549:BRAF-driven pediatric pilocytic astrocytoma model for preclinical drug testing.
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Selt F, Hohloch J, Hielscher T, Sahm F, Capper D, Korshunov A, Usta D, Brabetz S, Ridinger J, Ecker J, Oehme I, Gronych J, Marquardt V, Pauck D, Bächli H, Stiles CD, von Deimling A, Remke M, Schuhmann MU, Pfister SM, Brummer T, Jones DT, Witt O, and Milde T
- Subjects
- Antigens, Polyomavirus Transforming genetics, Blotting, Western, Cell Proliferation physiology, Child, Preschool, Drug Screening Assays, Antitumor, Gene Expression Profiling, Humans, Male, Oncogene Proteins, Fusion genetics, Polymerase Chain Reaction, Proto-Oncogene Proteins B-raf genetics, Transcriptome, Transduction, Genetic, Astrocytoma, Brain Neoplasms, Cell Culture Techniques, Cell Line, Tumor, Cellular Senescence physiology
- Abstract
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.
- Published
- 2017
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15. Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors.
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Längle D, Marquardt V, Heider E, Vigante B, Duburs G, Luntena I, Flötgen D, Golz C, Strohmann C, Koch O, and Schade D
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- Chemistry Techniques, Synthetic, Dihydropyridines chemical synthesis, HEK293 Cells, Humans, Models, Molecular, Protein Conformation, Transforming Growth Factor beta chemistry, Dihydropyridines chemistry, Dihydropyridines pharmacology, Drug Design, Quantitative Structure-Activity Relationship, Smad Proteins antagonists & inhibitors, Transforming Growth Factor beta antagonists & inhibitors
- Abstract
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 b-annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. 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 (R)-configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r(2) = 0.93) with a good predictive power (r(2)pred = 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 (e.g., 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 in vivo., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
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16. Effects of postretrieval-extinction learning on return of contextually controlled cued fear.
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Meir Drexler S, Merz CJ, Hamacher-Dang TC, Marquardt V, Fritsch N, Otto T, and Wolf OT
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- Adult, Electric Stimulation, Female, Galvanic Skin Response, Humans, Male, Young Adult, Conditioning, Classical, Cues, Extinction, Psychological, Fear, Memory
- Abstract
Reactivation of an already consolidated memory makes it labile for a period of several hrs, which are required for its reconsolidation. Evidence suggests that the return of conditioned fear through spontaneous recovery, reinstatement, or renewal can be prevented by blockading this reconsolidation process using pharmacological or behavioral interventions. Postretrieval-extinction learning has been shown to prevent the return of cued fear in humans using fear-irrelevant stimuli, as well as cued and contextual fear in rodents. The effects of postretrieval extinction on human contextually controlled cued fear to fear-relevant stimuli remain unknown, and are the focus of the present study. The experimental design was based on 3 consecutive days: acquisition, reactivation and extinction, and re-extinction. For the fear conditioning, 2 zoo frames served as different contexts, 5 fear-relevant stimuli (aversive animal pictures) served as conditioned stimuli (CS), electric shocks served as unconditioned stimuli (UCS). Expectancy ratings and skin-conductance response (SCR) were used as measures of fear responses; spontaneous recovery and renewal were used as indicators of the return of fear. The expectancy ratings and SCR results indicated spontaneous recovery on the third day, regardless of retrieval prior to extinction. No robust renewal effect was seen. It is suggested that the use of fear-relevant stimuli, the context salience, or reactivation context may explain the lack of reconsolidation effect. Our study indicates that the beneficial effects of postretrieval-extinction learning are sensitive to subtle methodological changes.
- Published
- 2014
- Full Text
- View/download PDF
17. Structure and function of the molecular chaperone Hsp104 from yeast.
- Author
-
Grimminger-Marquardt V and Lashuel HA
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid chemistry, Amyloid metabolism, Animals, Fungal Proteins genetics, Heat-Shock Proteins genetics, Humans, Huntington Disease genetics, Huntington Disease metabolism, Models, Molecular, Mutation, Parkinson Disease genetics, Parkinson Disease metabolism, Peptides genetics, Peptides toxicity, Prion Diseases genetics, Prion Diseases metabolism, Prions chemistry, Prions genetics, Prions metabolism, Protein Folding, alpha-Synuclein chemistry, alpha-Synuclein genetics, alpha-Synuclein metabolism, Fungal Proteins chemistry, Fungal Proteins metabolism, Heat-Shock Proteins chemistry, Heat-Shock Proteins metabolism, Protein Conformation
- Abstract
The molecular chaperone Hsp104 plays a central role in the clearance of aggregates after heat shock and the propagation of yeast prions. Hsp104's disaggregation activity and prion propagation have been linked to its ability to resolubilize or remodel protein aggregates. However, Hsp104 has also the capacity to catalyze protein aggregation of some substrates at specific conditions. Hence, it is a molecular chaperone with two opposing activities with respect to protein aggregation. In yeast models of Huntington's disease, Hsp104 is required for the aggregation and toxicity of polyglutamine (polyQ), but the expression of Hsp104 in cellular and animal models of Huntington's and Parkinson's disease protects against polyQ and alpha-synuclein toxicity. Therefore, elucidating the molecular determinants and mechanisms underlying the ability of Hsp104 to switch between these two activities is of critical importance for understanding its function and could provide insight into novel strategies aimed at preventing or reversing the formation of toxic protein aggregation in systemic and neurodegenerative protein misfolding diseases. Here, we present an overview of the current molecular models and hypotheses that have been proposed to explain the role of Hsp104 in modulating protein aggregation and prion propagation. The experimental approaches and the evidences presented so far in relation to these models are examined. Our primary objective is to offer a critical review that will inspire the use of novel techniques and the design of new experiments to proceed towards a qualitative and quantitative understanding of the molecular mechanisms underlying the multifunctional properties of Hsp104 in vivo., ((c) 2009 Wiley Periodicals, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
18. [Noise in animal housing--a review with special reference to pig housing].
- Author
-
Schäffer D, Marquardt V, Marx G, and von Borell E
- Subjects
- Animal Husbandry, Animals, Stress, Physiological etiology, Stress, Physiological veterinary, Swine Diseases etiology, Housing, Animal, Noise adverse effects, Swine physiology
- Abstract
The interpretation of research on noise assessment in animal housing is difficult as goals and methodology of assessment differ substantially between studies. Besides the differences in housing conditions and technology used for measuring noise, a lack of knowledge exists for intra- and interspecies communication, hearing ability and assessment of detrimental consequences following noise exposure. Due to the development of intensive production systems, pigs in all stages of housing are exposed to monotonous chronic noise as well as to a variety of intense noise events. The intention of this review is to document and compare the results of previous studies on noise assessment, in particular housing situations and to demonstrate the impact and significance of the noise problem for farm animal welfare, housing, design and management.
- Published
- 2001
19. What pathologists should know and be able to do in laboratory data processing and computers: general theory.
- Author
-
Hosty TA, Lundberg GD, Wertz RK, Krieg AF, Wertman BG, and Marquardt VC
- Subjects
- Computers, Information Systems, Laboratories, Pathology
- Published
- 1981
20. Request for proposal for a laboratory computer system--a proposed outline.
- Author
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Hosty TA, Lundberg GD, Krieg AF, Marquardt VC, Wertman BG, and Wertz RK
- Subjects
- Documentation, Computers, Laboratories organization & administration, Purchasing, Hospital
- Published
- 1981
21. What pathologists should know and be able to do in laboratory data processing and computers: software.
- Author
-
Wertman BG, Krieg AF, Lundberg GD, Marquardt VC, Hosty TA, and Wertz RK
- Subjects
- Pathology, Computers, Information Systems, Laboratories
- Published
- 1981
22. The LCADP classification of clinical lab data processing--an update.
- Author
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Krieg AF, Lundberg GD, Hosty TA, Marquardt VC, Wertman BG, and Wertz RK
- Subjects
- Systems Analysis, United States, Computers classification, Information Systems, Laboratories
- Abstract
The authors of this article review briefly their original classification for clinical laboratory data (February 1979), which they proposed as an aid in analyzing and solving data processing problems, and recommend some extensions based on recent experience.
- Published
- 1981
23. The current status of laboratory data processing.
- Author
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Wertman B, Marquardt VC, Krieg AF, Hosty TA, Wertz RK, and Lundberg GD
- Subjects
- Hospitals, Surveys and Questionnaires, United States, Computers statistics & numerical data, Laboratories
- Abstract
The CAP Laboratory Computer Applications and Data Processing Committee surveyed recently a random sample of participants in the CAP Survey Program to determine the current status of data processing in clinical laboratories. The results of the study, which confirm that laboratory computerization is a still new but growing movement, are presented in the following pages.
- Published
- 1980
24. What pathologists should know and be able to do in laboratory data processing and computers: peripheral devices and storages.
- Author
-
Wertz RK, Krieg AF, Wertman BG, Marquardt VC, Lundberg GD, and Hosty TA
- Subjects
- Pathology, Computers, Information Systems instrumentation, Laboratories organization & administration
- Abstract
This article is the second in a five-part educational series on laboratory data processing and computers. The authors describe the major components of peripheral storage and the limitations of input/output devices, and analyze in terms of laboratory workflow the type and placement of input/output devices. Preceding the article are competency areas and performance objectives, defined by the Laboratory Computer Applications and Data Processing Committee. Following the article are questions with which readers can test their understanding of the material. Next month the authors will focus on software.
- Published
- 1981
25. What every pathologist should know and be able to do in laboratory data processing and computers: relating to consultants.
- Author
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Marquardt VC, Wertz RK, Wertman BG, Hosty TA, Lundberg GD, and Krieg AF
- Subjects
- Computers, Consultants, Hospital Departments organization & administration, Laboratories organization & administration, Pathology Department, Hospital organization & administration
- Published
- 1982
26. What every pathologist should know and be able to do in laboratory data processing and computers: systems analysis and planning.
- Author
-
Krieg AF, Marquardt VC, Lundberg GD, Hosty TA, Wertz RK, and Wertman BG
- Subjects
- Hospitals, Computers, Laboratories, Systems Analysis
- Abstract
This article is the fourth in a five part series on laboratory data processing and computers. Preceding the article are enabling and performance objectives, defined by the Laboratory Computer Applications and Data Processing Committee, for the systems analysis and planning competency area. Following the article are questions with which readers can test their understanding of the material.
- Published
- 1982
27. A definition and classification of clinical laboratory data processing.
- Author
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Krieg AF, Lundberg GD, Hosty TA, Marquardt VC, Sinton EB, and Wertman BG
- Subjects
- Classification, Forms and Records Control, United States, Computers, Hospital Departments organization & administration, Laboratories organization & administration, Pathology Department, Hospital organization & administration, Systems Analysis
- Published
- 1979
28. So a laboratory computer system sounds like a good idea?
- Author
-
Hosty TA, Lundberg GD, Krieg AF, Marquardt VC, Sinton EB, and Wertman B
- Subjects
- Hospital Records, Information Systems, United States, Computers, Hospital Departments organization & administration, Laboratories organization & administration, Pathology Department, Hospital organization & administration
- Published
- 1979
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