In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model.
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.
New Agent and Innovative Therapy Program, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.
Libo
L
Zhang
Kristen M
KM
Smith
Amy L
AL
Chong
Diana
D
Stempak
Herman
H
Yeger
Paula
P
Marrano
Paul S
PS
Thorner
Meredith S
MS
Irwin
David R
DR
Kaplan
Sylvain
S
Baruchel
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib