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

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/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 T, R* 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 T. Tumour R* 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/Th-MYCN mice caused significant 4 % and 21 % tumour growth delay, and a significant 5 % reduction in native T 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 mice, revealed in situ using MRI. Native T is an early, sensitive and clinically translatable imaging biomarker of effective treatment response in neuroblastoma.