Abstract
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.
Highlights
Medulloblastoma is the most common malignant pediatric brain tumor
We provide clinical and preclinical evidence suggesting that Polo-like kinase 1 (PLK1) is a provocative molecular target for pediatric medulloblastoma that transcends molecular subtypes
These data prompted us to address whether there may be drugs in clinical trials for adult cancers that would be beneficial for combating Sonic Hedgehog (SHH) type tumors in children; we subtyped four medulloblastoma cell lines (ONS76, UW228, UW426, and Daoy)
Summary
Medulloblastoma is the most common malignant pediatric brain tumor. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). The advances in medical treatments have improved patient survival from 5% in the 1960s [1] to more than 70% for the standard-risk disease [2, 3]. 3), and almost all survivors will inevitably suffer from adverse, lifelong consequences from treatment. The 5-year survival rate for the high-risk disease is still dismal These undesirable effects are attributable to the detrimental impacts that surgical procedures, radiotherapy, and chemotherapy have on the developing brain [4]. There is an imperative need to identify novel therapeutics that could improve the cure rate while avoiding harmful side effects
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