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

2014; Impact Journals LLC; Volume: 5; Issue: 16 Linguagem: Inglês

10.18632/oncotarget.2240

1949-2553

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

Neuroblastoma Research and Treatments

// Rogerio B. Craveiro 1,* , Michael Ehrhardt 1,* , Martin I. Holst 2 , Thorsten Pietsch 2 and Dagmar Dilloo 1 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.