In Vivo anti-tumor and anti-metastatic activity of administration of sunitinib in preclinical neuroblastoma mouse model

Libo Zhang, Kristen Smith , Amy L Chong , Diana Stempak, Herman Yeger, Paula Marrano, Paul S Thorner, Meredith S Irwin, David R Kaplan and Sylvain Baruchel

Year 2009, Volume 11, Issue 5

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 hematopoetic 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 VEGF in NB and we showed that an anti-VEGFR2 antibody could induce sustained NB tumour suppression and regression. Sunitinib is a kinase inhibitor targeting platelet-derived growth factor receptors (PDGFRs) and VEGFRs, and therefore, a promising anti-angiogenic agent. In this study, we investigated the anti-tumor activity of sunitinib and its synergistic cytotoxicity with conventional (cyclophosphamide) and novel (rapamycin) therapies. Both NB cell lines and tumor initiating cells (TICs) from patient tumor samples were used in our in vitro and in vivo models for these drug testing. We show that sunitinib inhibits in vitro tumor cell proliferation and phosphorylation of VEGF receptors. It also inhibits tumor growth, angiogenesis and metastasis in tumor xenograft models. Low dose sunitinib (20mg/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 anti-tumor activity of sunitinib both in early stage of tumor formation and 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 neuroblastoma.

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