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• W2890916944 abstract "11578 Background: ES is a rare soft tissue sarcoma with two variants, i.e., the proximal and the distal. Retrospective data on the activity of anthracycline- and G-based regimens are available. EZH2 inhibitors, which target the INI1 pathway that is inactivated in ES, are currently being tested in clinical trial. Comparisons of these agents are not available and unlikely to be prospectively evaluated. We comparatively assess these agents in a proximal-type INI1-deleted ES PDX. Methods: A PDX model (ES-1) was established by subcutaneously xenotransplanting into immunodeficient (SCID) mice tumor fragments obtained from a patient with primary, proximal-type, INI1 deleted ES of the forearm. After tumor propagation in SCID mice for three consecutive passages, the PDX was considered established. Mice were randomized to receive D and I, as single agents or in combination (D+I), G and the EZH2 inhibitor EPZ-011989 (E) (8 mice/experimental group). Drug activity was assessed in terms of tumor volume inhibition (TVI%). RNA-seq was performed on samples obtained from patient primary tumor and from ES-1 before and after treatment with E. Results: As single agents, both D and I showed a modest antitumor effect. Conversely, D+I induced an almost complete tumor growth inhibition (max TVI: 94%). A comparable antitumor activity was caused by G (max TVI: 98%). E initially induced a tumor growth stabilization, followed by a progressive reduction of tumor volume starting from end of treatment (max TVI: 89%). Consistently with its mechanism of action, E inhibited trimethylation and increased acetylation of H3K27, as detected by Western Blot in tumor samples at different intervals from the end of mouse treatment. Analysis of RNAseq data is ongoing. Conclusions: Our preclinical results in a proximal-type ES INI1-deleted PDX model showed a strong and comparable antitumor activity for D+I, G and E. These data support clinical use of G and D+I and confirm that EZH2 is a therapeutic target in proximal-type ES. Experiments with D and G combined to E are planned. To which extent these preclinical findings can be extended to distal ES subtype is left to be defined." @default.
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• W2890916944 date "2018-05-20" @default.
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• W2890916944 title "Doxorubicin (D), gemcitabine (G), ifosfamide (I) and the EZH2 inhibitor EPZ-011989 in epithelioid sarcoma (ES): A comparison of different regimens in a patient-derived xenograft (PDX) model." @default.
• W2890916944 doi "https://doi.org/10.1200/jco.2018.36.15_suppl.11578" @default.
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