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IBL-302 对神经母细胞瘤的抗肿瘤作用。

Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma.

机构信息

Division of Pediatrics, Department of Clinical Sciences, Lund University, Lund, Sweden.

Department of Laboratory Medicine, Translational Cancer Research, Lund University Cancer Center, Lund University, Lund, Sweden.

出版信息

EMBO Mol Med. 2019 Aug;11(8):e10058. doi: 10.15252/emmm.201810058. Epub 2019 Jul 16.

DOI:10.15252/emmm.201810058
PMID:31310053
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6685085/
Abstract

The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor. Screening IBL-302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL-302 was more effective than single PI3K inhibition in vitro, and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels. IBL-302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho-proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL-302 treatment. While IBL-302 treatment alone reduced tumor growth in vivo, combination therapy with low-dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high-risk neuroblastoma.

摘要

PI3K 通路是癌症进展的主要驱动因素。然而，临床对 PI3K 抑制的耐药性很常见。IBL-302 是一种新型的高度特异的三靶 PIM、PI3K 和 mTOR 抑制剂。在代表 47 种肿瘤类型的 700 多个细胞系中筛选 IBL-302，确定神经母细胞瘤是 PIM/PI3K/mTOR 抑制的强候选物。IBL-302 在体外比单一的 PI3K 抑制更有效，并且 IBL-302 治疗神经母细胞瘤患者来源的异种移植（PDX）细胞诱导细胞凋亡、分化肿瘤细胞，并降低 N-Myc 蛋白水平。IBL-302 进一步增强了常见细胞毒性化疗药物顺铂、多柔比星和依托泊苷的作用。全基因组、蛋白质组和磷酸化蛋白质组分析确定了 IBL-302 治疗靶向的关键生物学过程，包括细胞迁移和凋亡。虽然 IBL-302 单独治疗可减少体内肿瘤生长，但与低剂量顺铂联合治疗可抑制神经母细胞瘤 PDX 生长。用 PIM/PI3K/mTOR 抑制补充常规化疗治疗有可能改善高危神经母细胞瘤儿童的临床结局并减少严重的晚期效应。

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