PO.CL06.02 · 临床研究
泛CLK/DYRK抑制剂SM09419延长一部分儿童髓母细胞瘤患者来源原位异种移植小鼠模型的动物生存期
The pan-CLK DYRK inhibitor SM09419 prolongs animal survival times in a subset of pediatric medulloblastoma patient-derived orthotopic xenograft mouse models
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摘要 Abstract
中文摘要
背景：异常RNA剪接促成儿童脑肿瘤中致癌性转录失调。SM09419是一种强效泛CLK/DYRK抑制剂，可调节可变剪接和Wnt相关信号通路。SM09419是Cirtuvivint（SM08502）的一个结构上密切相关的类似物，后者是Biosplice Therapeutics（TenaRx, Inc.）研发的另一种CLK/DYRK抑制剂，已在两项完成的用于成人实体瘤治疗的I期临床试验中进行研究（NCT03355066和NCT05084859），目前正在AML或MDS成人（NCT06484062）、软组织肉瘤（NCT07032285）、卵巢癌（NCT06856499）和小细胞肺癌（NCT07155200）中进行研究。本研究的目的是在一组患者来源原位异种移植（PDOX）模型中评估其作为单一CLK/DYRK靶向药物对不同分子亚型髓母细胞瘤（MB）的抗肿瘤疗效。
方法：11个MB PDOX模型，包括G3型（ICb-1572MB、ICb-1595MB、ICb-2555MB、ICb-5301MB）、SHH型（ICb-5610MB、ICb-3854MB、ICb-984MB、ICb-4989MB）和WNT型（ICb-1192MB、ICb-1140MB、ICb-S1218MB），接受SM09419处理（25 mg/kg，口服，每日一次，连续21天）。通过Gehan-Breslow-Wilcoxon检验评估动物生存期的变化。通过Visiopharm辅助的免疫组织化学对细胞增殖（Ki-67）和凋亡（cleaved-PARP1、cleaved-Caspase-3）进行定量评估。
结果：SM09419在三个MB模型中产生了显著的生存期延长，将中位生存期从ICb-1572MB（G3）的27天（对照）增至36天（治疗）（33.3%）（P = 0.0143）；ICb-5610MB（SHH）从38.0天增至46.0天（21.1%）（P = 0.0029）；ICb-3854MB（SHH）从154.0天增至219.0天（42.2%）（P = 0.0359），并伴有ICb-1572MB和ICb-5610MB中Ki-67的显著降低（P < 0.05）以及cleaved-PARP1和cleaved-Caspase-3水平的升高趋势（P > 0.05）。7个模型中未检测到动物生存期的显著变化（P > 0.05），而最后一个模型在药物治疗后表现出生存期缩短（P < 0.05）。
结论：SM09419在一部分以增殖活性降低为特征的MB PDOX模型中产生了显著的治疗疗效。我们的发现凸显了MB亚型之间的生物学异质性，并支持继续研究剪接调节性CLK/DYRK抑制剂作为儿童脑肿瘤潜在靶向疗法。
查看英文原文 English 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.
利益披露 Disclosure
X. Zhai, None..
M. S. Palacios, None..
T. Jiang, None..
A. Abdallah, None..
Y. Mei, None..
E. Ciolak, None..
N. Wadhwani, None..
A. Lenzen, None.