Abstract 1167: The pan-CLK DYRK inhibitor SM09419 prolongs animal survival times in a subset of pediatric medulloblastoma patient-derived orthotopic xenograft mouse models.

Abstract Background: Aberrant RNA splicing contributes to oncogenic transcriptional dysregulation in pediatric brain tumors. SM09419 is a potent pan-CLK/DYRK inhibitor that modulates alternative splicing and Wnt-related signaling pathways. SM09419 is a closely structurally related analog of Cirtuvivint (SM08502), another CLK/DYRK inhibitor from Biosplice Therapeutics, TenaRx, Inc., which has been studied in two completed Phase I clinical trials for treatment in adult solid tumors (NCT03355066 and NCT05084859), and is currently being studied in adults with AML or MDS (NCT06484062), Soft tissue sarcomas (NCT07032285), Ovarian cancer (NCT06856499) and Small cell lung cancer (NCT07155200).. The objective of this study is to evaluate antitumor efficacy as a single CLK/DYRK targeting agent in different molecular subtypes of medulloblastoma (MB) in a panel of patient-derived orthotopic xenograft (PDOX) models. Methods: Eleven MB PDOX models including G3 (ICb-1572MB, ICb-1595MB, ICb-2555MB, ICb-5301MB), SHH (ICb-5610MB, ICb-3854MB, ICb-984MB, ICb-4989MB) and WNT (ICb-1192MB, ICb-1140MB, ICb-S1218MB) were treated with SM09419 (25 mg/kg, oral, once daily for 21 days). Changes of animal survival times were assessed by Gehan-Breslow-Wilcoxon tests. Cell proliferation (Ki-67) and (apoptosis cleaved-PARP1, cleaved-Caspase-3) was quantitatively evaluated by Visiopharm-aided immunohistochemistry. Results: Significant extension of survival times were generated by SM09419 in three MB models, increasing median survival times from 27 days (control) to 36 days (treated) (33.3%) (P = 0.0143) in ICb-1572MB (G3); from 38.0 to 46.0 days (21.1%) (P = 0.0029) in ICb-5610MB (SHH) and from 154.0 days to 219.0 Days (42.2%) (P = 0.0359) in ICb-3854MB (SHH), accompanied by a significant reduction of Ki-67 (P 0.05) and increased trends in cleaved-PARP1 and cleaved-Caspase-3 levels (P 0.05) in ICb-1572MB and ICb-5610MB. No significant changes of animal survival times were detected in 7 models (P 0.05), while the last model exhibited decreased survival times (P 0.05) following drug treatment. Conclusions: SM09419 produced significant therapeutic efficacy a subset of MB PDOX models characterized by decreased proliferative activity. Our findings highlight the biological heterogeneity among MB subtypes and support continued investigation of splicing-modulatory CLK/DYRK inhibitors as potential targeted therapies for pediatric brain tumors. Citation Format: Xin (Alice) Zhai, Zilu Huang, Milagros Suarez Palacios, Tongchao Jiang, Aalaa Abdallah, Jinnan Chen, Yiming Mei, Emily Ciolak, Nitin Wadhwani, Alicia Lenzen, Yuchen Du, Xiao-Nan Li. The pan-CLK DYRK inhibitor SM09419 prolongs animal survival times in a subset of pediatric medulloblastoma patient-derived orthotopic xenograft mouse models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1167.