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  1. Book ; Online ; Thesis: Assessment of TRAIL sensitisation by IAP antagonist TL32711 in malignant melanoma and development of a framework for response prediction

    Vetma, Vesna [Verfasser] / Morrison, Markus [Akademischer Betreuer]

    2020  

    Author's details Vesna Vetma ; Betreuer: Markus Morrison
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language English
    Publisher Universitätsbibliothek der Universität Stuttgart
    Publishing place Stuttgart
    Document type Book ; Online ; Thesis
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  2. Article ; Online: Convergence of pathway analysis and pattern recognition predicts sensitization to latest generation TRAIL therapeutics by IAP antagonism.

    Vetma, Vesna / Guttà, Cristiano / Peters, Nathalie / Praetorius, Christian / Hutt, Meike / Seifert, Oliver / Meier, Friedegund / Kontermann, Roland / Kulms, Dagmar / Rehm, Markus

    Cell death and differentiation

    2020  Volume 27, Issue 8, Page(s) 2417–2432

    Abstract: Second generation TRAIL-based therapeutics, combined with sensitising co-treatments, have recently entered clinical trials. However, reliable response predictors for optimal patient selection are not yet available. Here, we demonstrate that a novel and ... ...

    Abstract Second generation TRAIL-based therapeutics, combined with sensitising co-treatments, have recently entered clinical trials. However, reliable response predictors for optimal patient selection are not yet available. Here, we demonstrate that a novel and translationally relevant hexavalent TRAIL receptor agonist, IZI1551, in combination with Birinapant, a clinically tested IAP antagonist, efficiently induces cell death in various melanoma models, and that responsiveness can be predicted by combining pathway analysis, data-driven modelling and pattern recognition. Across a panel of 16 melanoma cell lines, responsiveness to IZI1551/Birinapant was heterogeneous, with complete resistance and pronounced synergies observed. Expression patterns of TRAIL pathway regulators allowed us to develop a combinatorial marker that predicts potent cell killing with high accuracy. IZI1551/Birinapant responsiveness could be predicted not only for cell lines, but also for 3D tumour cell spheroids and for cells directly isolated from patient melanoma metastases (80-100% prediction accuracies). Mathematical parameter reduction identified 11 proteins crucial to ensure prediction accuracy, with x-linked inhibitor of apoptosis protein (XIAP) and procaspase-3 scoring highest, and Bcl-2 family members strongly represented. Applied to expression data of a cohort of n = 365 metastatic melanoma patients in a proof of concept in silico trial, the predictor suggested that IZI1551/Birinapant responsiveness could be expected for up to 30% of patient tumours. Overall, response frequencies in melanoma models were very encouraging, and the capability to predict melanoma sensitivity to combinations of latest generation TRAIL-based therapeutics and IAP antagonists can address the need for patient selection strategies in clinical trials based on these novel drugs.
    MeSH term(s) Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dipeptides/pharmacology ; Humans ; Indoles/pharmacology ; Inhibitor of Apoptosis Proteins/antagonists & inhibitors ; Inhibitor of Apoptosis Proteins/metabolism ; Neoplasm Metastasis ; Pattern Recognition, Automated ; TNF-Related Apoptosis-Inducing Ligand/pharmacology
    Chemical Substances Dipeptides ; Indoles ; Inhibitor of Apoptosis Proteins ; TNF-Related Apoptosis-Inducing Ligand ; birinapant (6O4Z07B57R)
    Language English
    Publishing date 2020-02-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-020-0512-5
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4230: Show issues Location:
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  3. Article ; Online: Optimization of an ex vivo gene transfer to the hamstrings tendons muscle remnants: potential for genetic enhancement of bone healing.

    Rod, Eduard / Matić, Igor / Antunović, Maja / Vetma, Vesna / Pavičić, Ivan / Hudetz, Damir / Marijanović, Inga / Primorac, Dragan / Ivković, Alan

    Croatian medical journal

    2019  Volume 60, Issue 3, Page(s) 201–211

    Abstract: Aim: To assess whether an adenoviral vector carrying the bone morphogenetic protein genes (Ad.BMP-2) can transduce human muscle tissue and direct it toward osteogenic differentiation within one hour.: Methods: This in vitro study, performed at the ... ...

    Abstract Aim: To assess whether an adenoviral vector carrying the bone morphogenetic protein genes (Ad.BMP-2) can transduce human muscle tissue and direct it toward osteogenic differentiation within one hour.
    Methods: This in vitro study, performed at the Department of Molecular Biology, Faculty of Science, Zagreb from 2012 to 2017, used human muscle tissue samples collected during anterior cruciate ligament reconstructions performed in St Catherine Hospital, Zabok. Samples from 28 patients were transduced with adenoviral vector carrying firefly luciferase cDNA (Ad.luc) by using different doses and times of transduction, and with addition of positive ions for transduction enhancement. The optimized protocol was further tested on muscle samples from three new patients, which were transduced with Ad.BMP-2. Released bone morphogenetic protein 2 (BMP-2) levels in osteogenic medium were measured every three days during a period of 21 days. Expression of osteogenic markers was measured at day 14 and 21. After 21 days of cultivation, muscle tissue was immunohistochemically stained for collagen type I detection (COL-I).
    Results: The new transduction protocol was established using 108 plaque-forming units (P<0.001) as an optimal dose of adenoviral vector and 30 minutes (P<0.001) as an optimal contact time. Positive ions did not enhance transduction. Samples transduced with Ad.BMP-2 according to the optimized protocol showed enhanced expression of osteogenic markers (P<0.050), BMP-2 (P<0.001), and COL I.
    Conclusion: This study confirms that Ad.BMP-2 can transduce human muscle tissue and direct it toward osteogenic differentiation within 30 minutes.
    MeSH term(s) Adenoviridae ; Adolescent ; Adult ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/metabolism ; Cell Differentiation/genetics ; Cells, Cultured ; Genetic Enhancement ; Genetic Vectors ; Humans ; Middle Aged ; Muscle, Skeletal/physiology ; Osteogenesis/genetics ; Tendons/physiology ; Transduction, Genetic ; Young Adult
    Chemical Substances BMP2 protein, human ; Bone Morphogenetic Protein 2
    Language English
    Publishing date 2019-06-12
    Publishing country Croatia
    Document type Journal Article
    ZDB-ID 1157623-6
    ISSN 1332-8166 ; 0353-9504
    ISSN (online) 1332-8166
    ISSN 0353-9504
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 187: Show issues Location:
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  4. Article ; Online: Examining the In Vitro Efficacy of the IAP Antagonist Birinapant as a Single Agent or in Combination With Dacarbazine to Induce Melanoma Cell Death.

    Vetma, Vesna / Rožanc, Jan / Charles, Emilie M / Hellwig, Christian T / Alexopoulos, Leonidas G / Rehm, Markus

    Oncology research

    2017  Volume 25, Issue 9, Page(s) 1489–1494

    Abstract: Antagonists of inhibitors of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumors. The IAP antagonist birinapant is currently being tested in phase II ... ...

    Abstract Antagonists of inhibitors of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumors. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the antitumor efficacy of dacarbazine in vitro, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5,400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression. Surprisingly, functionally relevant synergies or response potentiation in combination treatments was not observed, and only one cell line modestly responded to birinapant single treatment (approximately 16% cell death). Although we did not study the underlying resistance mechanisms or more complex in vivo scenarios in which dacarbazine/birinapant response synergies may still possibly manifest, our findings are nevertheless noteworthy because IAP antagonists were demonstrated to strongly enhance responses to DNA-damaging agents in cell lines of other cancer types under comparable experimental conditions in vitro.
    MeSH term(s) Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Dacarbazine/administration & dosage ; Dipeptides/administration & dosage ; Dipeptides/pharmacology ; Humans ; Indoles/administration & dosage ; Indoles/pharmacology ; Melanoma/drug therapy ; Melanoma/pathology ; Mutation ; Skin Neoplasms/drug therapy ; Skin Neoplasms/pathology
    Chemical Substances Dipeptides ; Indoles ; birinapant (6O4Z07B57R) ; Dacarbazine (7GR28W0FJI)
    Language English
    Publishing date 2017-03-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1114699-0
    ISSN 1555-3906 ; 0965-0407
    ISSN (online) 1555-3906
    ISSN 0965-0407
    DOI 10.3727/096504017X14897145996933
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3087: Show issues Location:
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  5. Article ; Online: Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity.

    Imaide, Satomi / Riching, Kristin M / Makukhin, Nikolai / Vetma, Vesna / Whitworth, Claire / Hughes, Scott J / Trainor, Nicole / Mahan, Sarah D / Murphy, Nancy / Cowan, Angus D / Chan, Kwok-Ho / Craigon, Conner / Testa, Andrea / Maniaci, Chiara / Urh, Marjeta / Daniels, Danette L / Ciulli, Alessio

    Nature chemical biology

    2021  Volume 17, Issue 11, Page(s) 1157–1167

    Abstract: Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could ... ...

    Abstract Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel-Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.
    MeSH term(s) Humans ; Proteolysis ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2021-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-021-00878-4
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    Zs.A 6251: Show issues Location:
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  6. Article ; Online: Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.

    Rožanc, Jan / Sakellaropoulos, Theodore / Antoranz, Asier / Guttà, Cristiano / Podder, Biswajit / Vetma, Vesna / Rufo, Nicole / Agostinis, Patrizia / Pliaka, Vaia / Sauter, Thomas / Kulms, Dagmar / Rehm, Markus / Alexopoulos, Leonidas G

    Cell death and differentiation

    2018  Volume 26, Issue 8, Page(s) 1365–1378

    Abstract: Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug ... ...

    Abstract Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug resistance and improve patient care. To this end, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified. In this study, we applied multiplex phosphoproteomic profiling across a panel of 24 melanoma cell lines with different disease-relevant mutations, to predict responsiveness to MEK inhibitor trametinib. Supported by multivariate statistical analysis and multidimensional pattern recognition algorithms, the responsiveness of individual cell lines to trametinib could be predicted with high accuracy (83% correct predictions), independent of mutation status. We also successfully employed this approach to case specifically predict whether individual melanoma cell lines could be sensitised to trametinib. Our predictions identified that combining MEK inhibition with selective targeting of c-JUN and/or FAK, using siRNA-based depletion or pharmacological inhibitors, sensitised resistant cell lines and significantly enhanced treatment efficacy. Our study indicates that multiplex proteomic analyses coupled with pattern recognition approaches could assist in personalising trametinib-based treatment decisions in the future.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Pyridones/pharmacology ; Pyrimidinones/pharmacology
    Chemical Substances Antineoplastic Agents ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN)
    Language English
    Publishing date 2018-10-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-018-0210-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4230: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  7. Article ; Online: A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.

    Kofink, Christiane / Trainor, Nicole / Mair, Barbara / Wöhrle, Simon / Wurm, Melanie / Mischerikow, Nikolai / Roy, Michael J / Bader, Gerd / Greb, Peter / Garavel, Géraldine / Diers, Emelyne / McLennan, Ross / Whitworth, Claire / Vetma, Vesna / Rumpel, Klaus / Scharnweber, Maximilian / Fuchs, Julian E / Gerstberger, Thomas / Cui, Yunhai /
    Gremel, Gabriela / Chetta, Paolo / Hopf, Stefan / Budano, Nicole / Rinnenthal, Joerg / Gmaschitz, Gerhard / Mayer, Moriz / Koegl, Manfred / Ciulli, Alessio / Weinstabl, Harald / Farnaby, William

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 5969

    Abstract: Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target ... ...

    Abstract Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
    MeSH term(s) Adenosine Triphosphatases/genetics ; Adenosine Triphosphatases/metabolism ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Humans ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proteolysis ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Von Hippel-Lindau Tumor Suppressor Protein/genetics ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism
    Chemical Substances Nuclear Proteins ; SMARCA2 protein, human ; Transcription Factors ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Von Hippel-Lindau Tumor Suppressor Protein (EC 2.3.2.27) ; Adenosine Triphosphatases (EC 3.6.1.-) ; SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; VHL protein, human (EC 6.3.2.-)
    Language English
    Publishing date 2022-10-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-33430-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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