Response of GEM models of neuroblastoma to cabozantinib assessed by multiparametric magnetic resonance imaging

Abstract

Background

In neuroblastoma MYCN amplification is associated with enhanced angiogenesis and poor survival. Mutations in the anaplastic lymphoma kinase (ALK) gene can occur with MYCN amplification, conferring a very poor prognosis. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF)/c-MET signalling are implicated in neuroblastoma progression. Cabozantinib has potent activity against VEGFR2 and MET.

Methods

The efficacy of cabozantinib against tumours arising in GEM models of high-risk neuroblastoma was assessed using multiparametric MRI. Tumour-bearing Th-MYCN and Th-ALK^F1174L/Th-MYCN mice were imaged prior to, 24 and 48 hrs after treatment with either 30mg/kg/day cabozantinib or vehicle. Treatment-induced changes in tumour volume, native T₁, R₂* and ADC were evaluated, and histological correlates sought. Additional Th-MYCN mice were treated daily for up to 28 days.

Results

Cabozantinib elicited significant 24 and 60 % growth delay 24 and 48 hrs after treatment in tumours in Th-MYCN mice, and a significant 6-8 % reduction in native T₁. Tumour R₂* was significantly reduced 48 hrs post-treatment. Significantly higher tumour necrosis and apoptosis, and significantly lower Ki67, CD34 and VEGFR2 staining, was determined from the cabozantinib-treated mice. Treatment of Th-ALK^F1174L/Th-MYCN mice caused significant 4 % and 21 % tumour growth delay, and a significant 5 % reduction in native T₁ at 48 hrs. Daily cabozantinib treatment of Th-MYCN mice elicited significant tumour growth delay over 7 days which translated into significant survival benefit.

Conclusion

Cabozantinib exhibits activity against neuroblastomas arising in both Th-MYCN and Th-MYCN/ALK^F1174L mice, revealed in situ using MRI. Native T₁ is an early, sensitive and clinically translatable imaging biomarker of effective treatment response in neuroblastoma.