Abstract A030: Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model

Abstract

Abstract Anagrelide is a phosphodiesterase 3A inhibitor that is used to treat essential thrombocythemia. The drug stabilizes the interaction of PDE3A and Schlafen 12 (SLFN12), resulting in complex stabilization, activation of SLFN12 RNase activity and cytotoxic effects in cancer cells. Gastrointestinal stromal tumors (GIST) exhibit high levels of PDE3A expression compared to other cancers or healthy tissue. Orally administered anagrelide has shown antitumor effects in patient-derived GIST xenograft (PDX) mouse models. In this study, we investigated the efficacy of subcutaneously administered, sustained-release anagrelide in UZLX-GIST2B, a PDX mouse model characterized by a KIT mutation in exon 9 and typical dose-dependent imatinib sensitivity. We assessed changes in tumor volume and evaluated histological drug responses including hyalinization, fibrosis, myxoid generation, and tumor necrosis. Anagrelide was administered either orally (2.5 mg/kg, twice a day) or subcutaneously (35 mg/kg and 70 mg/kg, every fourth day) for a duration of 11 days. Treatments with both 35 mg/kg and 70 mg/kg doses resulted in a significant reduction in average tumor volume compared to untreated control mice (both doses 25% vs.129%, P < 0.001) or mice treated with oral anagrelide (25% vs. 61%, P =0 .08, P < 0.05, respectively). The histological response in tumor tissue was positively correlated with dose level, and tumors treated with the highest dose exhibited grade 3 to 4 responses in all cases. These results suggest that sustained-release anagrelide holds promise as a therapeutic option for the treatment of GIST. Further preclinical studies are warranted to investigate the pharmacokinetics and toxicity of this treatment approach. Citation Format: Kirsi Toivanen, Luna De Sutter, Agnieszka Wozniak, Tom Böhling, Patrick Schöffski, Harri Sihto. Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A030.