Anagrelide for gastrointestinal stromal tumor

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.

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