2. Academic Validation
  3. Anagrelide for Gastrointestinal Stromal Tumor

Anagrelide for Gastrointestinal Stromal Tumor

  • Clin Cancer Res. 2019 Mar 1;25(5):1676-1687. doi: 10.1158/1078-0432.CCR-18-0815.
Olli-Pekka Pulkka 1,  Yemarshet K Gebreyohannes 2,  Agnieszka Wozniak 2,  John-Patrick Mpindi 3,  Olli Tynninen 4,  Katherine Icay 5,  Alejandra Cervera 5,  Salla Keskitalo 6,  Astrid Murumägi 3,  Evgeny Kulesskiy 3,  Maria Laaksonen 7,  Krister Wennerberg 3,  Markku Varjosalo 6,  Pirjo Laakkonen 8,  Rainer Lehtonen 5,  Sampsa Hautaniemi 5,  Olli Kallioniemi 3,  Patrick Schöffski 2,  Harri Sihto 1,  Heikki Joensuu 9 10
Affiliations

Affiliations

  • 1 Laboratory of Molecular Oncology, Research Programs Unit, Translational Cancer Biology, Department of Oncology, University of Helsinki, Helsinki, Finland.
  • 2 Laboratory of Experimental Oncology, Department of Oncology, KU Leuven and Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
  • 3 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
  • 4 Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland.
  • 5 Research Programs Unit, Genome-Scale Biology, Medicum and Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • 6 Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • 7 MediSapiens Ltd., Helsinki, Finland.
  • 8 Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
  • 9 Laboratory of Molecular Oncology, Research Programs Unit, Translational Cancer Biology, Department of Oncology, University of Helsinki, Helsinki, Finland. heikki.joensuu@hus.fi.
  • 10 Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
PMID: 30530703 DOI: 10.1158/1078-0432.CCR-18-0815
Abstract

Purpose: Gastrointestinal stromal tumor (GIST) is a common type of soft-tissue sarcoma. Imatinib, an inhibitor of KIT, platelet-derived growth factor receptor alpha (PDGFRA), 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 human tissue and Cancer samples, and PDE3A and PDE3B expression was studied using IHC on tissue microarrays (TMA) consisting of 630 formalin-fixed human tissue samples. GIST cell lines were screened for sensitivity to 217 Anticancer 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 with 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 also effective 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 Anticancer efficacy in GIST xenograft models and warrants further testing in clinical trials.

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