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  1. Article: The Role of the Hedgehog Pathway in Cholangiocarcinoma.

    Anichini, Giulia / Carrassa, Laura / Stecca, Barbara / Marra, Fabio / Raggi, Chiara

    Cancers

    2021  Volume 13, Issue 19

    Abstract: Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and, along with hepatocellular carcinoma (HCC), is the predominant type of primitive liver cancer in adults. The lack of understanding of CCA biology has slowed down the identification of ... ...

    Abstract Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and, along with hepatocellular carcinoma (HCC), is the predominant type of primitive liver cancer in adults. The lack of understanding of CCA biology has slowed down the identification of novel targets and the development of effective treatments. While tumors share some general characteristics, detailed knowledge of specific features is essential for the development of effectively tailored therapeutic approaches. The Hedgehog (HH) signaling cascade regulates stemness biology, embryonal development, tissue homeostasis, and cell proliferation and differentiation. Its aberrant activation has been associated with a variety of solid and hematological human malignancies. Several HH-inhibiting compounds have been indeed developed as potential anticancer agents in different types of tumors, with Smoothened and GLI inhibitors showing the most promising results. Beside its well-established function in other tumors, findings regarding the HH signaling in CCA are still controversial. Here we will give an overview of the most important clinical and molecular features of cholangiocarcinoma, and we will discuss the available evidence of the crosstalk between the HH signaling pathway and the cholangiocarcinoma cell biology.
    Language English
    Publishing date 2021-09-24
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13194774
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: DNA Damage Response Inhibitors in Cholangiocarcinoma: Current Progress and Perspectives.

    Gönül Geyik, Öykü / Anichini, Giulia / Ulukaya, Engin / Marra, Fabio / Raggi, Chiara

    Cells

    2022  Volume 11, Issue 9

    Abstract: Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and its incidence is dramatically increasing. The lack of understanding of the biology of this tumor has slowed down the identification of novel targets and the development of effective ... ...

    Abstract Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and its incidence is dramatically increasing. The lack of understanding of the biology of this tumor has slowed down the identification of novel targets and the development of effective treatments. Based on next generation sequencing profiling, alterations in DNA damage response (DDR)-related genes are paving the way for DDR-targeting strategies in CCA. Based on the notion of synthetic lethality, several DDR-inhibitors (DDRi) have been developed with the aim of accumulating enough DNA damage to induce cell death in tumor cells. Observing that DDRi alone could be insufficient for clinical use in CCA patients, the combination of DNA-damaging regimens with targeted approaches has started to be considered, as evidenced by many emerging clinical trials. Hence, novel therapeutic strategies combining DDRi with patient-specific targeted drugs could be the next level for treating cholangiocarcinoma.
    MeSH term(s) Bile Duct Neoplasms/drug therapy ; Bile Duct Neoplasms/genetics ; Bile Ducts, Intrahepatic ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/genetics ; DNA Damage ; DNA Repair ; Humans
    Language English
    Publishing date 2022-04-26
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells11091463
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Evaluation of coumarin-tagged deferoxamine as a Zr(IV)-based PET/fluorescence dual imaging probe.

    Romano, Giammarco Maria / Zizi, Virginia / Salvatore, Giulia / Bani, Riccardo / Mangoni, Monica / Nistri, Silvia / Anichini, Giulia / Simonini Steiner, Yschtar Tecla / Bani, Daniele / Bianchi, Antonio / Bencini, Andrea / Savastano, Matteo

    Journal of inorganic biochemistry

    2023  Volume 245, Page(s) 112259

    Abstract: Desferoxamine (DFO) is currently the golden standard chelator ... ...

    Abstract Desferoxamine (DFO) is currently the golden standard chelator for
    MeSH term(s) Deferoxamine/chemistry ; Radioisotopes/chemistry ; Tissue Distribution ; Ferric Compounds ; Fluorescence ; Positron-Emission Tomography/methods ; Chelating Agents/chemistry ; Coumarins ; Cell Line, Tumor
    Chemical Substances Deferoxamine (J06Y7MXW4D) ; Radioisotopes ; Ferric Compounds ; Chelating Agents ; Coumarins
    Language English
    Publishing date 2023-05-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 162843-4
    ISSN 1873-3344 ; 0162-0134
    ISSN (online) 1873-3344
    ISSN 0162-0134
    DOI 10.1016/j.jinorgbio.2023.112259
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 1730: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma.

    Anichini, Giulia / Raggi, Chiara / Pastore, Mirella / Carrassa, Laura / Maresca, Luisa / Crivaro, Enrica / Lottini, Tiziano / Duwe, Lea / Andersen, Jesper B / Tofani, Lorenzo / Di Tommaso, Luca / Banales, Jesus M / Arcangeli, Annarosa / Marra, Fabio / Stecca, Barbara

    Molecular cancer therapeutics

    2023  Volume 22, Issue 3, Page(s) 343–356

    Abstract: Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in ... ...

    Abstract Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2-M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA.
    MeSH term(s) Humans ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cholangiocarcinoma ; DNA Damage ; Hedgehog Proteins ; Protein-Tyrosine Kinases/genetics ; Receptors, G-Protein-Coupled/genetics ; Signal Transduction ; Smoothened Receptor/genetics ; Smoothened Receptor/metabolism ; Zinc Finger Protein GLI1/metabolism
    Chemical Substances Cell Cycle Proteins ; Hedgehog Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptors, G-Protein-Coupled ; Smoothened Receptor ; WEE1 protein, human (EC 2.7.10.2) ; Zinc Finger Protein GLI1
    Language English
    Publishing date 2023-02-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-22-0379
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth.

    Maresca, Luisa / Crivaro, Enrica / Migliorini, Francesca / Anichini, Giulia / Giammona, Alessandro / Pepe, Sara / Poggialini, Federica / Vagaggini, Chiara / Giannini, Giuseppe / Sestini, Serena / Borgognoni, Lorenzo / Lapucci, Andrea / Dreassi, Elena / Taddei, Maurizio / Manetti, Fabrizio / Petricci, Elena / Stecca, Barbara

    Pharmacological research

    2023  Volume 195, Page(s) 106858

    Abstract: Aberrant activation of Hedgehog (HH) signaling in cancer is the result of genetic alterations of upstream pathway components (canonical) or other oncogenic mechanisms (noncanonical), that ultimately concur to activate the zinc-finger transcription ... ...

    Abstract Aberrant activation of Hedgehog (HH) signaling in cancer is the result of genetic alterations of upstream pathway components (canonical) or other oncogenic mechanisms (noncanonical), that ultimately concur to activate the zinc-finger transcription factors GLI1 and GLI2. Therefore, inhibition of GLI activity is a good therapeutic option to suppress both canonical and noncanonical activation of the HH pathway. However, only a few GLI inhibitors are available, and none of them have the profile required for clinical development due to poor metabolic stability and aqueous solubility, and high hydrophobicity. Two promising quinoline inhibitors of GLI were selected by virtual screening and subjected to hit-to-lead optimization, thus leading to the identification of the 4-methoxy-8-hydroxyquinoline derivative JC19. This molecule impaired GLI1 and GLI2 activities in several cellular models interfering with the binding of GLI1 and GLI2 to DNA. JC19 suppressed cancer cell proliferation by enhancing apoptosis, inducing a strong anti-tumor response in several cancer cell lines in vitro. Specificity towards GLI1 and GLI2 was demonstrated by lower activity of JC19 in GLI1- or GLI2-depleted cancer cells. JC19 showed excellent metabolic stability and high passive permeability. Notably, JC19 inhibited GLI1-dependent melanoma xenograft growth in vivo, with no evidence of toxic effects in mice. These results highlight the potential of JC19 as a novel anti-cancer agent targeting GLI1 and GLI2.
    MeSH term(s) Animals ; Humans ; Mice ; Hedgehog Proteins/metabolism ; Kruppel-Like Transcription Factors/metabolism ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism ; Zinc Finger Protein GLI1/antagonists & inhibitors ; Zinc Finger Protein Gli2/antagonists & inhibitors ; Neoplasms/drug therapy ; Neoplasms/pathology
    Chemical Substances GLI1 protein, human ; GLI2 protein, human ; Hedgehog Proteins ; Kruppel-Like Transcription Factors ; Nuclear Proteins ; Transcription Factors ; Zinc Finger Protein GLI1 ; Zinc Finger Protein Gli2
    Language English
    Publishing date 2023-07-19
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1003347-6
    ISSN 1096-1186 ; 0031-6989 ; 1043-6618
    ISSN (online) 1096-1186
    ISSN 0031-6989 ; 1043-6618
    DOI 10.1016/j.phrs.2023.106858
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 721: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL.

    Pietrobono, Silvia / Anichini, Giulia / Sala, Cesare / Manetti, Fabrizio / Almada, Luciana L / Pepe, Sara / Carr, Ryan M / Paradise, Brooke D / Sarkaria, Jann N / Davila, Jaime I / Tofani, Lorenzo / Battisti, Ilaria / Arrigoni, Giorgio / Ying, Li / Zhang, Cheng / Li, Hu / Meves, Alexander / Fernandez-Zapico, Martin E / Stecca, Barbara

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 5865

    Abstract: Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 ... ...

    Abstract Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.
    MeSH term(s) Animals ; Gene Expression Regulation, Neoplastic ; Glycosylation ; Humans ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Mice, Nude ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; SOXB1 Transcription Factors/genetics ; SOXB1 Transcription Factors/metabolism ; Sialyltransferases/genetics ; Sialyltransferases/metabolism ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Transcription, Genetic ; Xenograft Model Antitumor Assays ; Zinc Finger Protein GLI1/genetics ; Zinc Finger Protein GLI1/metabolism ; beta-Galactoside alpha-2,3-Sialyltransferase ; Axl Receptor Tyrosine Kinase ; Melanoma, Cutaneous Malignant
    Chemical Substances GLI1 protein, human ; Multiprotein Complexes ; Proto-Oncogene Proteins ; SOX2 protein, human ; SOXB1 Transcription Factors ; Zinc Finger Protein GLI1 ; Sialyltransferases (EC 2.4.99.-) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; beta-Galactoside alpha-2,3-Sialyltransferase (EC 2.4.99.4) ; Axl Receptor Tyrosine Kinase
    Language English
    Publishing date 2020-11-17
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; 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/s41467-020-19575-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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