Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20 percent of all childhood brain tumors. New treatment strategies are needed to improve patient survival outcomes and to reduce adverse effects of current therapy. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway plays a key role in cellular metabolism, proliferation, survival and angiogenesis, and is often constitutively activated in human cancers, providing unique opportunities for anticancer therapeutic intervention. The aim of this study was to evaluate the pre-clinical activity of BKM120, a selective pan-class I PI3K inhibitor, on MB cell lines and primary samples. IC50 values of BKM120 in the twelve MB cell lines tested ranged from 0.279 to 4.38 μM as determined by cell viability assay. IncuCyte ZOOM Live-Cell Imaging system was used for kinetic monitoring of cytotoxicity of BKM120 and apoptosis in MB cells. BKM120 exhibited cytotoxicity in MB cells in a dose and time-dependent manner by inhibiting activation of downstream signaling molecules AKT and mTOR, and activating caspase-mediated apoptotic pathways. Furthermore, BKM120 decreased cellular glycolytic metabolic activity in MB cell lines in a dose-dependent manner demonstrated by ATP level per cell. In MB xenograft mouse study, DAOY cells were implanted in the flank of nude mice and treated with vehicle, BKM120 at 30 mg/kg and 60 mg/kg via oral gavage daily. BKM120 significantly suppressed tumor growth and prolonged mouse survival. These findings help to establish a basis for clinical trials of BKM120, which could be a novel therapy for the treatment of medulloblastoma patients.
Highlights
Improvements in the past 40 years have led to markedly improved survival rates of approximately 80% overall for pediatric cancers, patients with relapsed, rare and advanced stage tumors still have a very poor prognosis
We examined the mechanisms of BKM120 in a panel of both established and patient-derived primary medulloblastoma cell lines and found that BKM120 exhibits a strong anti-tumor efficacy both in vitro and in vivo, through caspase-mediated apoptosis
Koul et al reported that PARP and caspase-3 were only cleaved after BKM120 treatment in TP53 WT cells but not in TP53 mut/del cells [28]
Summary
Improvements in the past 40 years have led to markedly improved survival rates of approximately 80% overall for pediatric cancers, patients with relapsed, rare and advanced stage tumors still have a very poor prognosis. Medulloblastoma (MB) is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa. It is the most common malignant brain tumor in pediatric patients, accounting for 20% of all brain tumors in children. Five-year event-free survival rates for patients with high-risk MB are >60% and can be >80% in patients with standard-risk disease [2, 3]. Recurrence and progression of disease occurs in 15–20% of standard risk and 30– 40% of high risk patients, resulting in poor survival outcome [4]. There is a growing focus on treating MB based on the biology of the diseases rather than with “one size fits all” therapy
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