Prerna Kumar, Jessica Koach, Erin Nekritz, Sucheta Mukherjee, Benjamin S Braun, Steven G DuBois, Nicole Nasholm, Daphne Haas-Kogan, Katherine K Matthay, William A Weiss, Clay Gustafson, Youngho Seo
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引用次数: 0
Abstract
Background: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. We aimed to study the impact of AURKA inhibitors on DNA damage and tumor cell death in combination with 131I-MIBG therapy in a pre-clinical model of high-risk neuroblastoma.
Results: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels.
Conclusion: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.
抑制极光激酶 A 可增强高危神经母细胞瘤患者接受 131I-MIBG 治疗时的 DNA 损伤和肿瘤细胞死亡。
背景：神经母细胞瘤是最常见的颅外儿科实体瘤。131I-甲碘代苄基胍（MIBG）是一种对神经母细胞瘤肿瘤具有高度特异性的靶向放射性药物，可为广泛转移性疾病提供有效的放射治疗。极光激酶 A（AURKA）在神经母细胞瘤的有丝分裂和 MYCN 蛋白的稳定过程中发挥作用。我们的目的是在高危神经母细胞瘤临床前模型中研究 AURKA 抑制剂与 131I-MIBG 联合治疗对 DNA 损伤和肿瘤细胞死亡的影响：我们利用高危神经母细胞瘤体内模型，证实了 131I-MIBG 和 alisertib 对肿瘤生长的显著联合效应。在 MYCN 扩增的细胞系中，辐射和 AURKA A 抑制剂的联合作用增加了 DNA 损伤和细胞凋亡，降低了 MYCN 蛋白水平：结论：AURKA抑制剂与131I-MIBG联合治疗对耐药神经母细胞瘤模型有积极作用。
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