In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promisingin vitroandin vivoefficacy

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.

The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition

“…In keeping with the anti-tumorigenic capacity of Vandetanib, we observed a moderate reduction in phosphorylation of the VEGFR 2/3 and EGFR downstream signaling molecule STAT3 in Daoy and MEB-Med-8A. These observations confirm previous investigations delineating the importance of STAT3 pathway activation downstream of aberrant receptor tyrosine kinases signaling for tumorigenesis in medulloblastoma [ 26 – 28 ]. In view of the pronounced cytotoxic activity of Vandetanib in D283 Med and D341 Med, lack of concomitant downregulation of STAT3 phosphorylation indicates that in these cell lines other pathways e.g.…”

“…At this point it is noteworthy that inspite of the more narrow target-spectrum, the MKI Vandetanib displays similar in vitro efficacy against medulloblastoma as we have previously described for the broad-spectrum MKI Sorafenib and Pazopanib that inhibits amongst numerous other kinases also VEGFR 2 and 3 ( Supplementary Table 2 ). In an orthotopic xenograft modell of MYC-amplified medulloblastoma, Sorafenib and Pazopanib suppressed tumor growth with significantly prolonged survival [ 28 ]. This finding is in line with clinical phase I/II trials that document tumor responses of the VEGF antibody bevacizumab in combination with standard chemotherapy in patients suffering from recurrent medulloblastoma [ 37 ].…”

“…The current investigation therefore corroborates pre-clinical and clinical reports delineating a key role for VEGF signaling in medulloblastoma development and progression that can be exploited for therapy. As it may be inferred that the documented cytotoxic in vitro effects for Vandetanib also translate into anti-neoplastic efficacy in vivo as shown for the broad-spectrum MKI Sorafenib and Pazopanib, this approach warrants further evaluation [ 28 ].…”

Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site

“…Pazopanib as monotherapy given orally at 800 mg once daily is approved for the treatment of advanced renal cell carcinoma, soft tissue sarcoma and currently under investigation in multiple tumour types [2][3][4][5][6]. Pazopanib exhibits high inter-individual variability mainly due to its pharmacokinetic properties: low bioavailability (ranging from 14 to 39 % [7]), oxidative metabolism by CYP3A4 and substrate of P-glycoprotein and Breast Cancer Resistance Protein.…”

The PI3K inhibitor GDC-0941 displays promisingin vitro and in vivoefficacy for targeted medulloblastoma therapy

“…In medulloblastoma, increased copy number of the platelet-derived growth factor receptor alpha (PDGFRα) and overexpression of the epidermal growth factor receptor (EGFR) are associated with poor outcome [8] [9]. Also, inhibition of tyrosine receptor-activation suppresses cancer-promoting functions in vitro and in vivo [10] [11]. …”