Personalizing the treatment of pediatric medulloblastoma: Polo-like kinase PLK1 as a molecular target in high-risk children

Menée sur des échantillons tumoraux prélevés sur 122 patients pédiatriques atteints d'un médulloblastome, puis in vitro et in vivo, cette étude suggère l'intérêt d'une stratégie thérapeutique basée sur l'inhibition de la kinase PLK1

Résumé en anglais

Medulloblastoma (MB) is the most common malignant brain tumor in children. This disease is heterogeneous and it is comprised of four subtypes of MB (WNT, SHH, Group 3, and Group 4). An immediate goal is to identify novel molecular targets for the most aggressive forms of MB. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation making it a strong candidate for MB treatment. In this study, pediatric MBs were subtyped in two patient cohorts (Training cohort; n=65 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. Further, we screened a library of 129 compounds in clinical trials using a model of pediatric MB and determined that PLK1 inhibitors were the most promising class of agents against the growth of MB. In patient-derived primary MB isolates, the PLK1 small molecule inhibitor BI2536 suppressed the self-renewal of PLK1-high but not PLK1-low expressing cells. PLK1 inhibition prevented MB 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 MB-bearing mice with efficacy comparable to Headstart, a standard-of-care chemotherapy regime. We conclude that patients with MB expressing high levels of PLK1 are at elevated risk. These pre-clinical studies pave the way for improving the treatment of MB through PLK1 inhibition.