title: In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy.
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.
authors.affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany. These authors contributed equally to this work.
authors.forename: Rogerio B
authors.initials: RB
authors.lastname: Craveiro
authors.affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany. These authors contributed equally to this work.
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrhardt
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Martin I
authors.initials: MI
authors.lastname: Holst
authors.affiliation: Department of Neuropathology, University of Bonn, Bonn, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pietsch
authors.affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Dilloo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D007191:Indazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib