Portal de Periódicos da CAPES

The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition

2017; Impact Journals LLC; Volume: 8; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.14911

1949-2553

Rogerio B. Craveiro, Michael Ehrhardt, Julia Velz, Martin Olschewski, Barbara Goetz, Torsten Pietsch, Dagmar Dilloo,

Brain Metastases and Treatment

// Rogerio B. Craveiro 1, * , Michael Ehrhardt 1, * , Julia Velz 1 , Martin Olschewski 1 , Barbara Goetz 1 , Torsten Pietsch 2 and Dagmar Dilloo 1 1 Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, D-53113 Bonn, Germany 2 Department of Neuropathology, University of Bonn, D-53105 Bonn, Germany * These authors have contributed equally to this work Correspondence to: Rogerio B. Craveiro, email: Rogerio.craveiro@ukb.uni-bonn.de Keywords: medulloblastoma, Vandetanib, GDC-0941, targeted therapy, multi-kinase inhibitor (MKI) Received: July 27, 2016     Accepted: December 26, 2016     Published: January 31, 2017 ABSTRACT Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis. Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants.