Panobinostat, a histone deacetylase inhibitor, suppresses leptomeningeal seeding in a medulloblastoma animal model.

Ji Hoon Phi,Kyu-Chang Wang,Ji Yeoun Lee,Pil Ae Kwak,Do Won Hwang,Seung-Ki Kim,Seung Ah Choi

doi:10.18632/oncotarget.18132

Abstract

Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding.Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased. Panobinostat effectively down-regulated protein expression of CCND1 and ID3 which has been associated with leptomeningeal seeding of MB. After panobinostat treatment, neurophil-like cellular processes developed and expression of synaptophysin and NeuroD1 was increased, indicating neuronal differentiation. In MB leptomeningeal seeding in vivo model, the panobinostat-treated group showed significantly decreased spinal leptomeningeal seeding and a survival benefit.The findings demonstrate that panobinostat suppresses MB leptomeningeal seeding through the down-regulation of ID3 and the induction of neuronal differentiation. An HDAC inhibitor might be a potent treatment option for the treatment of MB patients with leptomeningeal seeding.

Highlights

Medulloblastoma (MB) is the most common malignant brain tumor in children
We evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding
The findings demonstrate that panobinostat suppresses MB leptomeningeal seeding through the down-regulation of ID3 and the induction of neuronal differentiation

Summary

Introduction

Medulloblastoma (MB) is the most common malignant brain tumor in children. The treatment outcomes of MB have been greatly improving for decades, but still a significant portion of patients suffer from tumor recurrence, which usually leads to fatality [1, 2]. 30–40% of MB patients already have leptomeningeal seeding of tumors at diagnosis [2]. This leptomeningeal seeding is a strong negative prognostic factor of the disease [3]. Leptomeningeal seeding is frequently accompanied with recurrent MB, and it conveys a dismal prognosis because there are few therapeutic options for such patients [4]

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Conclusion