Abstract
Deregulation of the Phosphoinositide 3-kinase (PI3K)/AKT signalling network is a hallmark of oncogenesis. Also medulloblastoma, the most common malignant brain tumor in children, is characterized by high levels of AKT phosphorylation and activated PI3K signalling in medulloblastoma is associated with enhanced cellular motility, survival and chemoresistency underscoring its role of as a potential therapeutic target. Here we demonstrate that GDC-0941, a highly specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancer, also displays anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines. Loss in cell viability is accompanied by reduced phosphorylation of AKT, a downstream target of PI3K. Furthermore, we show that GDC-0941 attenuates the migratory capacity of medulloblastoma cells and targets subpopulations expressing the stem cell marker CD133. GDC-0941 also synergizes with the standard medulloblastoma chemotherapeutic etoposide. In an orthotopic xenograft model of the most aggressive human medulloblastoma variant we document that oral adminstration of GDC-0941 impairs tumor growth and significantly prolongs survival. These findings provide a rational to further investigate GDC-0941 alone and in combination with standard chemotherapeutics for medulloblastoma treatment.
Highlights
Medulloblastoma is the most common malignant brain tumor in children
To analyse the potential of GDC-0941 in pediatric medulloblastoma cell lines we have used a panel of human medulloblastoma cell lines of which MEB-Med-8A, D283 Med, D341 exhibit distinct characteristics of the clinically most aggressive genetic group 3 variant
In a dose-response study the cytotoxic capacity of the Phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 was evaluated in the medulloblastoma cell lines by MTS assay at 48 h under standard growth conditions (Figure 1)
Summary
Medulloblastoma is the most common malignant brain tumor in children. Current medulloblastoma therapy comprises surgery, chemotherapy and radiotherapy in older children. Despite remarkably advances over the past decades, long-term survival still range from 40% to 70% [1]. Survivors often suffer from long-term treatment related neurological sequelae [2]. In cancerogenesis the Phosphoinositide 3-kinase (PI3K)/AKT signalling pathway has been identified as a key driver of cellular proliferation, migration and angiogenesis. This pertains to human medulloblastoma in which activation of PI3K/AKT signaling has been linked to enhanced tumor growth, metastasis and chemoresistancy [5,6,7]. As a target for cancer therapy PI3K/AKT is of particular interest as it serves as an integration node in a network of tumor-promoting signalling pathways including receptor tyrosine kinases
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