In Vivo Antitumor and Antimetastatic Activity of Sunitinib in Preclinical Neuroblastoma Mouse Model

Abstract

Neuroblastoma (NB) is one of the most common pediatric solid tumors originating from the neural crest lineage. Despite intensive treatment protocols including megatherapy with hematopoietic stem cell transplantation, the prognosis of NB patients remains poor. More effective therapeutics are required. High vascularity has been described as a feature of aggressive, widely disseminated NB. Our previous work demonstrated the overexpression of vascular endothelial growth factor (VEGF) in NB, and we showed that an anti-VEGF receptor (VEGFR-2) antibody could induce sustained NB tumor suppression and regression. Sunitinib is a kinase inhibitor targeting platelet-derived growth factor receptors and VEGFRs and, therefore, a promising antiangiogenic agent. In this study, we investigated the antitumor activity of sunitinib and its synergistic cytotoxicity with conventional (cyclophosphamide) and novel (rapamycin) therapies. Both NB cell lines and tumor-initiating cells from patient tumor samples were used in our in vitro and in vivo models for these drug testing. We show that sunitinib inhibits tumor cell proliferation and phosphorylation of VEGFRs. It also inhibits tumor growth, angiogenesis, and metastasis in tumor xenograft models. Low-dose sunitinib (20 mg/kg) demonstrates synergistic cytotoxicity with an mTOR inhibitor, rapamycin, which is more effective than the traditional chemotherapeutic drug, cyclophosphamide. These preclinical studies provide the evidence of antitumor activity of sunitinib both in the early stage of tumor formation and in the progressive metastatic disease. These studies also provide the framework for clinical trial of sunitinib, alone and in combination with conventional and novel therapies to increase efficacy and improve patient outcome in NB.

Multiple receptor tyrosine kinases regulate HIF-1α and HIF-2α in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors

“…A recent preclinical study by Zhang et al (2009) demonstrates that sunitinib is effective at inhibiting the in vivo growth and metastasis of neuroblastoma. Our data are in agreement with this report and extends these findings, providing a mechanism by which sunitinib decreases angiogenesis and invasiveness of tumor cells.…”

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

“…Cell viability was assessed by Alamar Blue assay as previously described (37). Alamar Blue cell proliferation assay is based on a reducing environment that indicates metabolically active cells.…”

“…On the day of the test, cells were exposed to increasing concentrations of evofosfamide and topotecan either as single agents or combined treatment for 72 hours. Alamar Blue was added to a final concentration of 5%, incubated for 4 hours at 37 C and quantitated on a plate reader at 530/590 nm. IC 50 was determined by GraphPad Prism software.…”

Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome

“…Lapatinib was dissolved in 0.5% hydroxypropyl methylcellulose and 1% Tween80 as described (Konecny et al 2006). Sunitinib (Sigma Aldrich) was prepared in dextrose water (Zhang et al 2009). Mice were gavaged with lapatinib (100 mg/kg) and sunitinib (40 mg/kg) QD (Sun et al 2011).…”