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  1. Article ; Online: Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine.

    Barry, Evan R / Simov, Vladimir / Valtingojer, Iris / Venier, Olivier

    Cells

    2021  Volume 10, Issue 10

    Abstract: The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to ... ...

    Abstract The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1-4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein-protein interaction (PPI) with TEAD1-4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ-TEAD-dependent transcription in cancer.
    MeSH term(s) Animals ; Clinical Trials as Topic ; Humans ; Medical Oncology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/metabolism ; Regenerative Medicine ; Signal Transduction
    Chemical Substances Protein Kinase Inhibitors ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2021-10-11
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10102715
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Refined high-content imaging-based phenotypic drug screening in zebrafish xenografts.

    Sturtzel, C / Grissenberger, S / Bozatzi, P / Scheuringer, E / Wenninger-Weinzierl, A / Zajec, Z / Dernovšek, J / Pascoal, S / Gehl, V / Kutsch, A / Granig, A / Rifatbegovic, F / Carre, M / Lang, A / Valtingojer, I / Moll, J / Lötsch, D / Erhart, F / Widhalm, G /
    Surdez, D / Delattre, O / André, N / Stampfl, J / Tomašič, T / Taschner-Mandl, S / Distel, M

    NPJ precision oncology

    2023  Volume 7, Issue 1, Page(s) 44

    Abstract: Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in ... ...

    Abstract Zebrafish xenotransplantation models are increasingly applied for phenotypic drug screening to identify small compounds for precision oncology. Larval zebrafish xenografts offer the opportunity to perform drug screens at high-throughput in a complex in vivo environment. However, the full potential of the larval zebrafish xenograft model has not yet been realized and several steps of the drug screening workflow still await automation to increase throughput. Here, we present a robust workflow for drug screening in zebrafish xenografts using high-content imaging. We established embedding methods for high-content imaging of xenografts in 96-well format over consecutive days. In addition, we provide strategies for automated imaging and analysis of zebrafish xenografts including automated tumor cell detection and tumor size analysis over time. We also compared commonly used injection sites and cell labeling dyes and show specific site requirements for tumor cells from different entities. We demonstrate that our setup allows us to investigate proliferation and response to small compounds in several zebrafish xenografts ranging from pediatric sarcomas and neuroblastoma to glioblastoma and leukemia. This fast and cost-efficient assay enables the quantification of anti-tumor efficacy of small compounds in large cohorts of a vertebrate model system in vivo. Our assay may aid in prioritizing compounds or compound combinations for further preclinical and clinical investigations.
    Language English
    Publishing date 2023-05-18
    Publishing country England
    Document type Journal Article ; Review
    ISSN 2397-768X
    ISSN 2397-768X
    DOI 10.1038/s41698-023-00386-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: TEAD Inhibitors Sensitize KRAS

    Tammaccaro, Salvina Laura / Prigent, Philippe / Le Bail, Jean-Christophe / Dos-Santos, Odette / Dassencourt, Laurent / Eskandar, Myriam / Buzy, Armelle / Venier, Olivier / Guillemot, Jean-Claude / Veeranagouda, Yaligara / Didier, Michel / Spanakis, Emmanuel / Kanno, Tokuwa / Cesaroni, Matteo / Mathieu, Stephane / Canard, Luc / Casse, Alhassan / Windenberger, Fanny / Calvet, Loreley /
    Noblet, Laurence / Sidhu, Sukhvinder / Debussche, Laurent / Moll, Jurgen / Valtingojer, Iris

    Pharmaceuticals (Basel, Switzerland)

    2023  Volume 16, Issue 4

    Abstract: ... ...

    Abstract KRAS
    Language English
    Publishing date 2023-04-06
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph16040553
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: YAP1 is essential for malignant mesothelioma tumor maintenance.

    Calvet, Loreley / Dos-Santos, Odette / Spanakis, Emmanuel / Jean-Baptiste, Véronique / Le Bail, Jean-Christophe / Buzy, Armelle / Paul, Pascal / Henry, Christophe / Valence, Sandrine / Dib, Colette / Pollard, Jack / Sidhu, Sukhvinder / Moll, Jürgen / Debussche, Laurent / Valtingojer, Iris

    BMC cancer

    2022  Volume 22, Issue 1, Page(s) 639

    Abstract: Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are ... ...

    Abstract Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.
    MeSH term(s) Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Humans ; Mesothelioma/pathology ; Mesothelioma, Malignant ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; YAP-Signaling Proteins
    Chemical Substances Phosphoproteins ; YAP-Signaling Proteins ; YAP1 protein, human
    Language English
    Publishing date 2022-06-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041352-X
    ISSN 1471-2407 ; 1471-2407
    ISSN (online) 1471-2407
    ISSN 1471-2407
    DOI 10.1186/s12885-022-09686-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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