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Anagrelide for Gastrointestinal Stromal Tumor

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Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Anagrelide for gastrointestinal stromal tumor Olli-Pekka Pulkka1, Yemarshet K. Gebreyohannes2, Agnieszka Wozniak2, John-Patrick Mpindi3, Olli Tynninen4, Katherine Icay5, Alejandra Cervera5, Salla Keskitalo6, Astrid Murumägi3, Evgeny Kulesskiy3, Maria Laaksonen7, Krister Wennerberg3, Markku Varjosalo6, Pirjo Laakkonen8, Rainer Lehtonen5, Sampsa Hautaniemi5, Olli Kallioniemi3, Patrick Schöffski2, Harri Sihto1*, and Heikki Joensuu1,9* 1Laboratory of Molecular Oncology, Research Programs Unit, Translational Cancer Biology, Department of Oncology, University of Helsinki, Helsinki, Finland. 2Laboratory of Experimental Oncology, Department of Oncology, KU Leuven and Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. 3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland 4Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland. 5Research Programs Unit, Genome-Scale Biology, Medicum and Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 6Institute of Biotechnology, University of Helsinki, Helsinki, Finland. 7MediSapiens Ltd., Helsinki, Finland 8Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland. 9Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 *Shared authorship Running title: Anagrelide for GIST Keywords: Gastrointestinal stromal tumor, Phosphodiesterase 3, Anagrelide, Imatinib Financial Support: This study was supported by the Academy of Finland, Center of Excellence for Translational Cancer Biology, Cancer Society of Finland, Jane and Aatos Erkko Foundation, HUCH Research Funds, Sigrid Juselius Foundation, Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (Belgium), Ida Montin Foundation, Emil Aaltonen Foundation, and Luise and Henrik Kuningas Foundation. Disclosure of Potential Conflicts of Interest: O.P. Pulkka, O. Kallioniemi, H. Sihto, and H. Joensuu own stocks of Sartar Therapeutics and are board members. H. Joensuu has a co- appointment at Orion Pharma, and has received fees from Orion Pharma and Neutron Therapeutics Ltd. Other authors declare no conflict of interest. Corresponding Author: Heikki Joensuu, MD, Comprehensive Cancer Center, Helsinki University Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland; fax: (+358) 9 471 74202; Phone: (+358) 40 72 10438; e-mail: [email protected]. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 Translational Relevance GISTs frequently harbor either mutated KIT or PDGFRA that encode a constitutively activated receptor tyrosine kinase. Imatinib, an inhibitor of KIT, PDGFRA, and a few other kinases, revolutionized the systemic treatment of GIST, but second mutations that inhibit imatinib and other tyrosine kinase inhibitors from binding to the activated kinases often eventually emerge leading to GIST progression. Enzymes of the phosphodiesterase 3 family (PDE3A and PDE3B) are highly expressed in GIST compared to many other types of human cancer, which may open an opportunity for an efficient targeted therapy. Anagrelide, a PDE3- specific modulator marketed for the treatment of thrombocytemia, decreases GIST cell proliferation, and promotes their apoptosis in vitro. Anagrelide inhibited GIST growth in patient-derived mouse xenograft models. Anagrelide may have therapeutic value in the treatment of GIST. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 Abstract Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft tissue sarcoma. Imatinib, an inhibitor of KIT, PDFGRA and a few other tyrosine kinases, is highly effective for GIST, but advanced GISTs frequently progress on imatinib and other approved tyrosine kinase inhibitors. We investigated phosphodiesterase 3 (PDE3) as a potential therapeutic target in GIST cell lines and xenograft models. Experimental Design: The GIST gene expression profile was interrogated in the MediSapiens IST Online transcriptome database comprising of human tissue and cancer samples, and PDE3A and PDE3B expression was studied using immunohistochemistry on tissue microarrays (TMAs) consisting of 630 formalin-fixed human tissue samples. GIST cell lines were screened for sensitivity to 217 anti-cancer compounds, and the efficacy of PDE inhibitors on GIST was further studied in GIST cell lines and patient-derived mouse xenograft models. Results: GISTs expressed PDE3A and PDE3B frequently compared to other human normal or cancerous tissues both in the in silico database and the TMAs. Anagrelide was identified as the most potent of the PDE3 modulators evaluated. It reduced cell viability, promoted cell death, and influenced cell signaling in GIST cell lines. Anagrelide inhibited tumor growth in GIST xenograft mouse models. Anagrelide was effective also in a GIST xenograft mouse model with KIT exon 9 mutation that may pose a therapeutic challenge, as these GISTs require a high daily dose of imatinib. Conclusions: PDE3A and PDE3B are frequently expressed in GIST. Anagrelide had anti- cancer efficacy in GIST xenograft models, and warrants further testing in clinical trials. Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 Introduction Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma that arises from the gastrointestinal tract. GISTs frequently harbor aberrant KIT or platelet derived growth factor receptor alpha (PDGFRA) that encode constitutively activated receptor tyrosine kinases (1, 2), but a minority of GISTs lack a mutation in these genes (3). Most GIST patients with a KIT mutation or a PDGFRA mutation can be effectively treated with tyrosine kinase inhibitors such as imatinib or other agents (4), but second mutations conferring drug resistance emerge frequently leading to GIST progression (5). Sunitinib and regorafenib, the approved second-line and third-line agents for advanced GIST, are effective, but the median time to disease progression was 6 months or less with these agents in the pivotal randomized trials (6, 7). Therefore, there is a need for novel effective agents for the treatment of patients with advanced GIST. Phosphodiesterase (PDE) 3A and 3B are cyclic nucleotide phosphodiesterases that regulate the intracellular concentration, localization, and signaling of cyclic AMP (cAMP), and/or cyclic GMP (cGMP) by controlling their degradation (8). cAMP and cGMP signaling regulate various physiological processes, including cell proliferation and differentiation, inflammation, gene expression, apoptosis, and metabolic pathways (9-11). PDE3A is expressed in the smooth muscle, platelets, and cardiac tissues, and it is involved in platelet aggregation and in the regulation of the blood pressure, cardiac function, and oocyte meiosis (8, 12). PDE3B is frequently expressed in cells that are important in energy homeostasis, such as adipocytes and hepatocytes (8). PDE3B is important especially in insulin signaling (13). Some types of cancer, such as chronic lymphocytic leukemia (CLL) and colorectal cancer, express low levels of cAMP as a consequence of overexpression of PDEs (14, 15), and inhibition of various PDEs has antitumor effects in several cancer cell lines (16). High Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 7, 2018; DOI: 10.1158/1078-0432.CCR-18-0815 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6 PDE3A expression is associated with Sclaffen12 (SLFN12) expression in GIST (17, 18). In one study, the PDE3 inhibitor cilostazol reduced the GIST882 cell line viability, and the PDE3A SLFN12 interaction was suggested to have a role in cell death (17). Anagrelide hydrochloride targets the PDE3 enzyme family and reduces the peripheral blood platelet numbers by inhibiting megakaryopoiesis in the bone marrow (19, 20), and is used for the treatment of essential thrombocythemia (21, 22). Anagrelide inhibits the cyclic AMP phosphodiesterase activity elevating the cAMP levels in platelets (23, 24) In the present study we investigated the role of PDE3 in
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  • Selective PDE4 Inhibitors As Potent Anti-Inflammatory Drugs for The

    Selective PDE4 Inhibitors As Potent Anti-Inflammatory Drugs for The

    Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 100(Suppl. I): 131-136, 2005 131 Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases Vincent Lagente/+, Corinne Martin-Chouly, Elisabeth Boichot, Marco A Martins*, Patrica MR Silva* INSERM U620, Faculté de Pharmacie, Université de Rennes 1, 2, avenue du Professeur Léon Bernard, 35043, Rennes Cedex, Rennes, France *Laboratório de Inflamação, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz-Fiocruz, Rio de Janeiro, RJ, Brasil Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smoke- induced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstrutive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-β1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.