The PI3K inhibitor GDC-0941 displays promising in vitro and in vivo efficacy for targeted medulloblastoma therapy
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Michael Ehrhardt1,*, Rogerio B. Craveiro1,*, Martin I. Holst2, Torsten Pietsch2, Dagmar Dilloo1
1Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, D-53113 Bonn, Germany
2Department of Neuropathology, University of Bonn, 53105 Bonn, Germany
* These authors have contributed equally to this work
Rogério B. Craveiro, e-mail: Rogerio.email@example.com
Keywords: medulloblastoma, GDC-0941, PI3K inhibitor, targeted therapy, c-myc
Received: August 13, 2014 Accepted: November 08, 2014 Published: December 06, 2014
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.
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