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

Craveiro RB, Ehrhardt M, Holst MI, Pietsch T, Dilloo D - Oncotarget (2014)

Bottom Line: 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.Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany. These authors contributed equally to this work.

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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In medulloblastoma Pazopanib and Sorafenib treatment leads to a dose-dependent reduction of cell viabilityThe cell lines MEB-Med-8A, D283 Med, Daoy and D341 Med were treated with increasing concentrations of Pazopanib and Sorafenib. Areas shaded in grey indicate the range of the respective MKI concentrations detectable in patient's plasma. The vehicle DMSO served as control. After 48h of drug exposure the cell viability was assessed by MTS assay. Values below an asterisk are significantly different from the control (*p<0,05). Each experiment was performed in triplicates and repeated four times.
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Figure 1: In medulloblastoma Pazopanib and Sorafenib treatment leads to a dose-dependent reduction of cell viabilityThe cell lines MEB-Med-8A, D283 Med, Daoy and D341 Med were treated with increasing concentrations of Pazopanib and Sorafenib. Areas shaded in grey indicate the range of the respective MKI concentrations detectable in patient's plasma. The vehicle DMSO served as control. After 48h of drug exposure the cell viability was assessed by MTS assay. Values below an asterisk are significantly different from the control (*p<0,05). Each experiment was performed in triplicates and repeated four times.

Mentions: In a dose-response study the cytotoxic potency of Pazopanib and Sorafenib was assessed in the medulloblastoma cell lines Daoy, MEB-Med-8A, D283 Med and D341 Med (Figure 1). For comparative assessment of cell viability by MTS assay, MKI concentrations were chosen to reflect the range of different plasma levels observed in patients for MKIs namely 10 μM for Sorafenib and 15 μM for Pazopanib [21-22]. The vehicle DMSO served as control. At the lowest concentration of 0.5 μM, all 4 medulloblastoma cell lines proved itself entirely MKI-resistant but responded significantly to higher MKI concentrations. At 15 μM Pazopanib and 10 μM Sorafenib showed comparable efficacy in 3 of 4 medulloblastoma cell lines as documented by low level residual cell viability (Pazopanib: MEB-Med-8A 22.5±3.3%, D283 Med 56.7±4%, Daoy 45.7±10.2%; Sorafenib: MEB-Med-8A 21.1±1.7%, D283 Med 26±3.5%, Daoy 36.8±9.9%). When exposing D341 Med to the same concentration of Pazopanib and Sorafenib only a marginal growth suppressive effect was observed (Pazopanib: D341 Med 88±4.2%; Sorafenib: D341 Med 86.5±6.3%)


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

Craveiro RB, Ehrhardt M, Holst MI, Pietsch T, Dilloo D - Oncotarget (2014)

In medulloblastoma Pazopanib and Sorafenib treatment leads to a dose-dependent reduction of cell viabilityThe cell lines MEB-Med-8A, D283 Med, Daoy and D341 Med were treated with increasing concentrations of Pazopanib and Sorafenib. Areas shaded in grey indicate the range of the respective MKI concentrations detectable in patient's plasma. The vehicle DMSO served as control. After 48h of drug exposure the cell viability was assessed by MTS assay. Values below an asterisk are significantly different from the control (*p<0,05). Each experiment was performed in triplicates and repeated four times.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196191&req=5

Figure 1: In medulloblastoma Pazopanib and Sorafenib treatment leads to a dose-dependent reduction of cell viabilityThe cell lines MEB-Med-8A, D283 Med, Daoy and D341 Med were treated with increasing concentrations of Pazopanib and Sorafenib. Areas shaded in grey indicate the range of the respective MKI concentrations detectable in patient's plasma. The vehicle DMSO served as control. After 48h of drug exposure the cell viability was assessed by MTS assay. Values below an asterisk are significantly different from the control (*p<0,05). Each experiment was performed in triplicates and repeated four times.
Mentions: In a dose-response study the cytotoxic potency of Pazopanib and Sorafenib was assessed in the medulloblastoma cell lines Daoy, MEB-Med-8A, D283 Med and D341 Med (Figure 1). For comparative assessment of cell viability by MTS assay, MKI concentrations were chosen to reflect the range of different plasma levels observed in patients for MKIs namely 10 μM for Sorafenib and 15 μM for Pazopanib [21-22]. The vehicle DMSO served as control. At the lowest concentration of 0.5 μM, all 4 medulloblastoma cell lines proved itself entirely MKI-resistant but responded significantly to higher MKI concentrations. At 15 μM Pazopanib and 10 μM Sorafenib showed comparable efficacy in 3 of 4 medulloblastoma cell lines as documented by low level residual cell viability (Pazopanib: MEB-Med-8A 22.5±3.3%, D283 Med 56.7±4%, Daoy 45.7±10.2%; Sorafenib: MEB-Med-8A 21.1±1.7%, D283 Med 26±3.5%, Daoy 36.8±9.9%). When exposing D341 Med to the same concentration of Pazopanib and Sorafenib only a marginal growth suppressive effect was observed (Pazopanib: D341 Med 88±4.2%; Sorafenib: D341 Med 86.5±6.3%)

Bottom Line: 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.Thus, we identified Pazopanib as a new promising candidate for a rational clinical assessment for targeted paediatric medulloblastoma therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Hematology and Oncology, Center for Pediatrics, University of Bonn Medical Center, Bonn, Germany. These authors contributed equally to this work.

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.

Show MeSH
Related in: MedlinePlus