Abstract
BackgroundMYCN-amplification in high-grade Neuroblastoma (NB) tumors correlates with increased vascularization and therapy resistance. This study combines an anti-angiogenic approach with targeting NB metabolism for treatment.Methods and ResultsMetronomic cyclophosphamide (MCP) monotherapy significantly inhibited NB growth and prolonged host survival. Growth inhibition was more pronounced in MYCN-amplified xenografts. Immunohistochemical evaluation of this subtype showed significant decrease in blood vessel density and intratumoral hemorrhage accompanied by blood vessel maturation and perivascular fibrosis. Up-regulation of VEGFA was not sufficient to compensate for the effects of the MCP regimen. Reduced Bcl-2 expression and increased caspase-3 cleavage were evident. In contrast non MYCN-amplified tumors developed resistance, which was accompanied by Bcl-2-up-regulation. Combining MCP with a ketogenic diet and/or calorie-restriction significantly enhanced the anti-tumor effect. Calorie-restricted ketogenic diet in combination with MCP resulted in tumor regression in all cases.ConclusionsOur data show efficacy of combining an anti-angiogenic cyclophosphamide dosing regimen with dietary intervention in a preclinical NB model. These findings might open a new front in NB treatment.
Highlights
Neuroblastoma (NB) represents the most common extracranial solid childhood cancer
Inhibition of NB tumor growth by Metronomic cyclophosphamide (MCP) in combination with dietary intervention In an effort to exploit a potential synergism of targeting vascular supply and cancer cell metabolism, we chose to combine dietary intervention with MCP
MCP induced significant growth inhibition (p < 0.001) of NB xenografts of both cell lines tested from day 9 onward and extended survival (p < 0.001) compared to the corresponding standard diet group without MCP (SD group w/o without chemotherapy (CTx); Figure 1)
Summary
Marked biological and clinical heterogeneity, pose strong challenges to optimizing therapeutic interventions for individual cases. Among others biological risk factors include MYCN status, tumor histology, cancer cell DNA content and defined segmental chromosomal aberrations [1,2,3,4,5]. In combination with historical clinical data, tumor biology allows clinicians to guide therapy by stratifying patients into internationally accepted risk groups [6, 7]. In low- and intermediate-risk groups, with overall survival rates above 90%, recent studies have been focusing on reducing therapeutic toxicity. For patients in the high-risk group, improving treatment efficacy is still central with overall survival rates close to 50% despite multimodal therapy protocols [1]. MYCN-amplification in high-grade Neuroblastoma (NB) tumors correlates with increased vascularization and therapy resistance. This study combines an anti-angiogenic approach with targeting NB metabolism for treatment
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