Authors' Affiliations: Department of Pediatrics; Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine; Division of Pediatric Neurosurgery, Department of Surgery, BC Children's Hospital, University of British Columbia; Department of Pathology and Laboratory Medicine, Centre for Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia; Division of Neurosurgery, Department of Surgery, Faculty of Health Sciences, McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton; The Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario; Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) Laboratory for Pre-Clinical and Drug Discovery Studies, Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada; and Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Res. 2013 Nov 15;73(22):6734-44. doi: 10.1158/0008-5472.CAN-12-4331. Epub 2013 Sep 9.
Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition.
髓母细胞瘤是儿童中最常见的恶性脑肿瘤。这种疾病具有异质性，由四种亚型的髓母细胞瘤组成[WNT、Sonic Hedgehog（SHH）、Group 3 和 Group 4]。目前的一个主要目标是确定最具侵袭性的髓母细胞瘤的新分子靶点。Polo 样激酶 1（PLK1）是一种致癌激酶，可控制细胞周期和增殖，使其成为治疗髓母细胞瘤的强有力候选药物。在这项研究中，我们使用 NanoString nCounter 分析对两个患者队列（发现队列，n = 63 例患者；验证队列，n = 57 例患者）中的小儿髓母细胞瘤进行了亚型分类，并评估了 PLK1 mRNA。我们通过 Cox 回归分析确定，SHH 和 Group 3 亚型与儿童不良预后独立相关，PLK1 也是如此。此外，我们使用小儿髓母细胞瘤模型筛选了临床前试验中的 129 种化合物库，发现 PLK1 抑制剂是针对髓母细胞瘤生长最有前途的一类药物。在患者来源的原发性髓母细胞瘤分离物中，PLK1 小分子抑制剂 BI2536 抑制了高 PLK1 表达的细胞的自我更新，但对低 PLK1 表达的细胞没有抑制作用。PLK1 抑制可防止髓母细胞瘤细胞增殖、自我更新、细胞周期进程，并诱导细胞凋亡。相比之下，BI2536 对正常神经干细胞的生长没有影响。最后，BI2536 延长了荷瘤小鼠的生存期，其疗效可与 Headstart（一种标准的化疗方案）相媲美。我们的结论是，表达高水平 PLK1 的髓母细胞瘤患者风险增加。这些临床前研究为通过 PLK1 抑制改善髓母细胞瘤的治疗铺平了道路。
