RG-7388、CM-272和SGI-1027的体内比较评估以确定表观遗传靶向作为治疗高危神经母细胞瘤有效策略

Background: High-risk neuroblastoma remains a therapeutic challenge due to its chemoresistance, epigenetic modification, and TP53 pathway dysregulation. SK-N-AS cells, which harbor TP53 mutations and exhibit highly aggressive behavior, provide a clinically relevant model for evaluating novel epigenetic and apoptotic pathway-targeting agents. This study investigated the therapeutic efficacy of the MDM2 inhibitor (RG-7388), the dual DNMT1/G9a inhibitor (CM-272), and the DNMT inhibitor (SGI-1027) in an SK-N-AS xenograft mouse model. Methods: Athymic Nu/Nu mice bearing subcutaneous SK-N-AS tumors were randomized into treatment groups and administered RG-7388, CM-272, SGI-1027, or vehicle control (DMSO) according to an optimized dosing schedule. Tumor volumes, body weight, survival rate, and treatment-related toxicity were monitored over the study period. Excised tumors were analyzed for cell-cycle arrest markers, DNA-methylation regulators, apoptotic mediators, and histone acetylation/methylation levels via qRT-PCR and Western blot. Results: Treatment of Cell Derived Xenograft (CDX) animals with CM-272 significantly reduced tumor growth compared to control. Interestingly, treatment with RG-7388 also induced potent tumor suppression but exhibited a less durable response compared to CM-272. The anti-cancer effects produced by CM-272 was robust by showing significant reduction in tumor volume with minimal toxicity, accompanied by marked up-regulation of cell-cycle arrest markers, apoptotic mediators. In addition, a significant increase in the histone acetylation levels, which often serve as DNA/histone methylation regulators, indicated strong epigenetic reprogramming. Mechanistically, both CM-272 and SGI-1027 exhibited strong apoptotic activation, while RG-7388 primarily removed MDM2-associated stress signaling, despite the mutant/null status of TP53 in SK-N-AS cells. Survival analysis showed that CM-272 prolonged survival the most, followed by RG-7388 and SGI-1027. Conclusion: Epigenetic targeting of DNMT and G9a using CM-272 produced the strongest anti-tumor and survival benefit in the SK-N-AS CDX model, outperforming both RG-7388 and SGI-1027. CM-272's ability to simultaneously inhibit DNMT1 and G9a, appears to reduce repressive chromatin marks, and activate apoptosis cascade that highlights its translational potential for treating TP53 -mutant and epigenetically driven neuroblastoma. These initial findings suggest advancing preclinical optimization and combination-therapy strategies involving CM-272 for high-risk neuroblastoma. Acknowledgements: This work was supported by the National Pediatric Cancer Foundation (NPCF), the Florida Department of Health through a Bankhead-Coley Infrastructure Grant, and the Royal Dames of Cancer Research, Inc., Ft. Lauderdale, Florida.