Preclinical models for neuroblastoma: establishing a baseline for treatment

Background

Preclinical models of pediatric cancers are essential for testing newchemotherapeutic combinations for clinical trials. The most widely usedgenetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse.This neuroblastoma-prone mouse recapitulates many of the features of humanneuroblastoma. Limitations of this model include the low frequency of bonemarrow metastasis, the lack of information on whether the gene expressionpatterns in this system parallels human neuroblastomas, the relatively slowrate of tumor formation and variability in tumor penetrance on differentgenetic backgrounds. As an alternative, preclinical studies are frequentlyperformed using human cell lines xenografted into immunocompromised mice,either as flank implant or orthtotopically. Drawbacks of this system includethe use of cell lines that have been in culture for years, the inappropriatemicroenvironment of the flank or difficult, time consuming surgery fororthotopic transplants and the absence of an intact immune system.

Principal Findings

Here we characterize and optimize both systems to increase their utility forpreclinical studies. We show that TH-MYCN mice develop tumors in theparaspinal ganglia, but not in the adrenal, with cellular and geneexpression patterns similar to human NB. In addition, we present a newultrasound guided, minimally invasive orthotopic xenograft method. Thisinjection technique is rapid, provides accurate targeting of the injectedcells and leads to efficient engraftment. We also demonstrate that tumorscan be detected, monitored and quantified prior to visualization usingultrasound, MRI and bioluminescence. Finally we develop and test a“standard of care” chemotherapy regimen. This protocol, which isbased on current treatments for neuroblastoma, provides a baseline forcomparison of new therapeutic agents.

Significance

The studies suggest that use of both the TH-NMYC model of neuroblastoma andthe orthotopic xenograft model provide the optimal combination for testingnew chemotherapies for this devastating childhood cancer.