bl-4162a and Gastrointestinal-Stromal-Tumors

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.. 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.. GISTs expressed PDE3A and PDE3B frequently compared with other human normal or cancerous tissues both in the. PDE3A and PDE3B are frequently expressed in GIST. Anagrelide had anticancer efficacy in GIST xenograft models and warrants further testing in clinical trials.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cyclic Nucleotide Phosphodiesterases, Type 3; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gastrointestinal Stromal Tumors; High-Throughput Screening Assays; Humans; Mice; Platelet Aggregation Inhibitors; Quinazolines; Signal Transduction; Xenograft Model Antitumor Assays