Oncotarget

Research Papers:

In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy

Rogerio B. Craveiro _, Michael Ehrhardt, Martin I. Holst, Thorsten Pietsch and Dagmar Dilloo

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Oncotarget. 2014; 5:7149-7161. https://doi.org/10.18632/oncotarget.2240

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Abstract

Rogerio B. Craveiro1,*, Michael Ehrhardt1,*, Martin I. Holst2, Thorsten Pietsch2 and Dagmar Dilloo1

1 Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany

2 Department of Neuropathology, University of Bonn, Bonn, Germany

* These authors contributed equally to this work

Correspondence:

Rogério B. Craveiro, email:

Keywords: Medulloblastoma, Sorafenib, Pazopanib, Targeted therapy, Multi-kinase inhibitor (MKI)

Received: May 05, 2014 Accepted: July 21, 2014 Published: July 22, 2014

Abstract

Regardless of the recent advances in cytotoxic therapies, 30% of children diagnosed with medulloblastoma. succumb to the disease. Therefore, novel therapeutic approaches are warranted. Here we demonstrate that Pazopanib a clinically approved multi-kinase angiogenesis inhibitor (MKI) inhibits proliferation and apoptosis in medulloblastoma cell lines. Moreover, Pazopanib profoundly attenuates medulloblastoma cell migration, a prerequisite for tumor invasion and metastasis. In keeping with the observed anti-neoplastic activity of Pazopanib, we also delineate reduced phosphorylation of the STAT3 protein, a key regulator of medulloblastoma proliferation and cell survival. Finally, we document profound in vivo activity of Pazopanib in an orthotopic mouse model of the most aggressive c-myc amplified human medulloblastoma variant. Pazopanib reduced the growth rate of intracranial growing medulloblastoma and significantly prolonged the survival. Furthermore, to put these results into a broader perspective we analysed Pazopanib side by side with the MKI Sorafenib. Both compounds share a similar target profile but display different pharmacodynamics and pharmacokinetics with distinct cytotoxic activity in different tumor entities. Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.


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