BMI1 is a therapeutic target in recurrent medulloblastoma
BMI1 is a therapeutic target in recurrent medulloblastoma
复制标题
DOI：
10.1038/s41388-018-0549-9
复制
发表时间：
2019-03-07
期刊：
影响因子：
8
通讯作者：
Singh, Sheila K.
中科院分区：
文献类型：
--
作者：
Bakhshinyan, David;Venugopal, Chitra;Singh, Sheila K.
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤，占新诊断的儿童中枢神经系统恶性肿瘤的20%。尽管多模式治疗的进展使5年生存率达到80%，但MB仍然是儿童癌症死亡率的主要原因。在这项工作中，我们将表观遗传调节因子BMI 1描述为治疗复发性人类第3组MB的新治疗靶点，这是一种儿童脑肿瘤，除了姑息治疗外几乎没有其他治疗选择。基于原发性、未经治疗的肿瘤的基因组谱的复发性MB患者的当前临床试验将提供有限的临床益处，因为复发性转移性MB与其原发性肿瘤在遗传上高度不同。使用针对BMI 1的小分子抑制剂PTC-028，我们能够证明在体外MB干细胞的自我更新的完全消融。当给予异种移植有患者肿瘤的小鼠时，我们观察到局部和转移区室中的肿瘤负荷显著降低，随后存活率增加，而没有神经毒性。引人注目的是，一系列体内再移植测定证明，在将PTC-028处理的细胞再移植到第二受体小鼠脑中后，复发MB细胞的肿瘤引发能力显著降低。由于第3组MB通常是转移性的，并且在复发时一致致命，目前没有或计划进行靶向治疗试验，因此有效的靶向药物将迅速过渡到临床试验。
Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.