Abstract
Ependymomas in children can arise throughout all compartments of the central nervous system (CNS). Highly malignant paediatric ependymoma subtypes are Group A tumours of the posterior fossa (PF-EPN-A) and RELA-fusion positive (ST-EPN-RELA) tumours in the supratentorial compartment. It was repeatedly reported in smaller series that accumulation of p53 is frequently observed in ependymomas and that immunohistochemical staining correlates with poor clinical outcome, while TP53 mutations are rare. Our TP53 mutation analysis of 130 primary ependymomas identified a mutation rate of only 3%. Immunohistochemical analysis of 398 ependymomas confirmed previous results correlating the accumulation of p53 with inferior outcome. Among the p53-positive ependymomas, the vast majority exhibited a RELA fusion leading to the hypothesis that p53 inactivation might be linked to RELA positivity.In order to assess the potential of p53 reactivation through MDM2 inhibition in ependymoma, we evaluated the effects of Actinomycin-D and Nutlin-3 treatment in two preclinical ependymoma models representing the high-risk subtypes PF-EPN-A and ST-EPN-RELA. The IC-50 of the agent as determined by metabolic activity assays was in the lower nano-molar range (0.2–0.7 nM). Transcriptome analyses of high-dose (100 nM), low-dose (5 nM) and non-treated cells revealed re-expression of p53 dependent genes including p53 upregulated modulator of apoptosis (PUMA) after low-dose treatment. At the protein level, we validated the Actinomycin-D induced upregulation of PUMA, and of p53 interaction partners MDM2 and p21. Proapoptotic effects of low-dose application of the agent were confirmed by flow cytometry. Thus, Actinomycin-D could constitute a promising therapeutic option for ST-EPN-RELA ependymoma patients, whose tumours frequently exhibit p53 inactivation.
Highlights
Ependymomas are glial brain tumours probably arising from the subventricular zone and accounting for approximately 12% of all paediatric intracranial malignancies [1, 2]
In order to assess the potential of p53 reactivation through MDM2 inhibition in ependymoma, we evaluated the effects of Actinomycin-D and Nutlin-3 treatment in two preclinical ependymoma models representing the high-risk subtypes PF-EPN-A and ST-EPN-RELA
When correlating p53 status with subgroup information, which was available for 102 samples (ST-EPN-RELA (n = 38), PF-EPN-A (n = 60) and PF-EPN-B (n = 17)), it was striking that 89% (n = 34/38) of the supratentorial RELApositive tumours exhibited p53 accumulation (Figure 1C)
Summary
Ependymomas are glial brain tumours probably arising from the subventricular zone and accounting for approximately 12% of all paediatric intracranial malignancies [1, 2]. Based on previously reported results of chemotherapeutic regimens across several studies, a clear therapeutic efficacy of this treatment modality has yet to be demonstrated [3], leaving complete resection followed by radiotherapy the only curative and indispensable therapeutic option for these tumours. Lepto-meningeal dissemination occurring with an incidence of 9% to 20% [9], as well as local tumour progression comprise the main clinical challenges leading to a 5 year overall survival rate of only around 60% for all ependymomas [10]. To achieve the goal of increasing the overall survival rates, while simultaneously reducing serious longterm morbidity, the fact that ependymomas in different compartments are distinct diseases exhibiting pronounced intertumoural heterogeneity needs to be taken into account [11]. According to the recent WHO grading system, differentiation criteria between grade II and III ependymomas demonstrate great uncertainty, their reliability as prognostic factors remains doubtful [6, 12, 13]
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