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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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Related in: MedlinePlus

Pazopanib and Sorafenib delay tumor growth in vivo and prolong the survival of mice bearing intracranial human medulloblastomaIn a orthotopic xenograft mouse model we analysed whether Pazopanib and Sorafenib could inhibit medulloblastoma growth in vivo. For this purpose 2×104 MEB-Med-8A cells were transplanted into the cerebellum of mice to establish tumors. The tumor growth was analyzed by bioluminescent imagining after 1, 2, 3 and 4 weeks. One week after transplantation mice were treated with 60 mg/kg of Pazopanib and 30 mg/kg of Sorafenib once daily by gavage until they developed symptoms. Figure 7a depicts the normalized tumor growth delay while figure 7b shows the survival of treated and untreated animals via Kaplan-Meyer curve. Pazopanib and Sorafenib treatment prolonged the survival of medulloblastoma bearing mice significantly.
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Figure 7: Pazopanib and Sorafenib delay tumor growth in vivo and prolong the survival of mice bearing intracranial human medulloblastomaIn a orthotopic xenograft mouse model we analysed whether Pazopanib and Sorafenib could inhibit medulloblastoma growth in vivo. For this purpose 2×104 MEB-Med-8A cells were transplanted into the cerebellum of mice to establish tumors. The tumor growth was analyzed by bioluminescent imagining after 1, 2, 3 and 4 weeks. One week after transplantation mice were treated with 60 mg/kg of Pazopanib and 30 mg/kg of Sorafenib once daily by gavage until they developed symptoms. Figure 7a depicts the normalized tumor growth delay while figure 7b shows the survival of treated and untreated animals via Kaplan-Meyer curve. Pazopanib and Sorafenib treatment prolonged the survival of medulloblastoma bearing mice significantly.

Mentions: In an orthotopic mouse model we analyzed the capacity of Pazopanib and Sorafenib to inhibit human medulloblastoma growth in vivo (Figure 7). For this purpose 2×104 lentivirally transduced MEB-Med-8A cells stably expressing luciferase were transplanted into the cerebellum of immunocompromised mice resulting in reliable tumor formation as early as one week post transplantation. Animals with established tumors were treated with 60 mg/kg of Pazopanib and 30 mg/kg of Sorafenib respectively. Tumor growth was monitored via bioluminescent imagining and mice showing clinical impairment due to tumor progression were taken from the experiment. Animals treated with Pazopanib (31 days; median) and Sorafenib (29 days) displayed delayed tumor growth and survived significantly longer than control animals (22 days).


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)

Pazopanib and Sorafenib delay tumor growth in vivo and prolong the survival of mice bearing intracranial human medulloblastomaIn a orthotopic xenograft mouse model we analysed whether Pazopanib and Sorafenib could inhibit medulloblastoma growth in vivo. For this purpose 2×104 MEB-Med-8A cells were transplanted into the cerebellum of mice to establish tumors. The tumor growth was analyzed by bioluminescent imagining after 1, 2, 3 and 4 weeks. One week after transplantation mice were treated with 60 mg/kg of Pazopanib and 30 mg/kg of Sorafenib once daily by gavage until they developed symptoms. Figure 7a depicts the normalized tumor growth delay while figure 7b shows the survival of treated and untreated animals via Kaplan-Meyer curve. Pazopanib and Sorafenib treatment prolonged the survival of medulloblastoma bearing mice significantly.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Pazopanib and Sorafenib delay tumor growth in vivo and prolong the survival of mice bearing intracranial human medulloblastomaIn a orthotopic xenograft mouse model we analysed whether Pazopanib and Sorafenib could inhibit medulloblastoma growth in vivo. For this purpose 2×104 MEB-Med-8A cells were transplanted into the cerebellum of mice to establish tumors. The tumor growth was analyzed by bioluminescent imagining after 1, 2, 3 and 4 weeks. One week after transplantation mice were treated with 60 mg/kg of Pazopanib and 30 mg/kg of Sorafenib once daily by gavage until they developed symptoms. Figure 7a depicts the normalized tumor growth delay while figure 7b shows the survival of treated and untreated animals via Kaplan-Meyer curve. Pazopanib and Sorafenib treatment prolonged the survival of medulloblastoma bearing mice significantly.
Mentions: In an orthotopic mouse model we analyzed the capacity of Pazopanib and Sorafenib to inhibit human medulloblastoma growth in vivo (Figure 7). For this purpose 2×104 lentivirally transduced MEB-Med-8A cells stably expressing luciferase were transplanted into the cerebellum of immunocompromised mice resulting in reliable tumor formation as early as one week post transplantation. Animals with established tumors were treated with 60 mg/kg of Pazopanib and 30 mg/kg of Sorafenib respectively. Tumor growth was monitored via bioluminescent imagining and mice showing clinical impairment due to tumor progression were taken from the experiment. Animals treated with Pazopanib (31 days; median) and Sorafenib (29 days) displayed delayed tumor growth and survived significantly longer than control animals (22 days).

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