The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition
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Rogerio B. Craveiro1,*, Michael Ehrhardt1,*, Julia Velz1, Martin Olschewski1, Barbara Goetz1, Torsten Pietsch2 and 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, D-53105 Bonn, Germany
*These authors have contributed equally to this work
Rogerio B. Craveiro, email: Rogerio.firstname.lastname@example.org
Keywords: medulloblastoma, Vandetanib, GDC-0941, targeted therapy, multi-kinase inhibitor (MKI)
Received: July 27, 2016 Accepted: December 26, 2016 Published: January 31, 2017
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.
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