Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children

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 ¼ 63 patients; validation cohort, n ¼ 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, selfrenewal, 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. Cancer Res; 73(22); 6734-44. Ó2013 AACR.

Repurposing the Antihelmintic Mebendazole as a Hedgehog Inhibitor

“…DAOY cells have a gene expression profile consistent with a type 2 (Hh-subtype) medulloblastoma and accordingly exhibit elevated Hh signaling (40). In these cells, MBZ caused a reduction in GLI1 expression with an IC 50 =516 ±81 nM (SEM; Fig.…”

“…S1B). Notably, DAOY xenografts exhibit large cell morphology (40), which in naturally-evolving tumors is associated with poor outcomes (41). …”

Molecular mechanisms and therapeutic targets in pediatric brain tumors

“…The observation of increased PI3K pathway activity in tumors that develop resistance to SMOis (63,64), along with reports of recurrent mutations affecting this pathway (12,42), has suggested that PI3K inhibition may be an important strategy for preventing or overcoming resistance of SHH-MB. Finally, preclinical studies have suggested that Polo-like kinase inhibitors may be particularly effective in SHH-MB (71,72). The heterogeneity of driver mutations and resistance mechanisms even within the SHH-MB subgroup suggests that careful patient selection and a diversity of therapeutic approaches will be necessary to effectively target this disease.…”

Inhibition of Plk1 represses androgen signaling pathway in castration-resistant prostate cancer

“…[11][12][13][14] BI2536 is an ATP-competitive Plk1 kinase inhibitor and has been used in phase II clinical studies in breast cancer, endometrial cancer, head and neck cancer, melanoma, ovarian cancer and sarcoma. 15 In prostate cancer, Plk1 knockdown by RNAi causes induction of mitotic catastrophe, 16 suggesting that Plk1 might be a target and BI2536 might be a potential drug of PCa treatment.…”