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

in Neoplasia (New York, N.Y.) by Gilberto S Almeida, Philippa King, Albert Hallsworth, Hannah Webber, Sergey Popov, Susana Miranda, Orli Yogev, Andrew D J Pearson, Louis Chesler, Yann Jamin, Simon P Robinson

TLDR

  • Cabozantinib effectively delays tumour growth and improves survival in high-risk neuroblastoma models, with potential implications for future treatment options.

Abstract

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. 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. 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 Tat 48 hrs. Daily cabozantinib treatment of Th-MYCN mice elicited significant tumour growth delay over 7 days which translated into significant survival benefit. Cabozantinib exhibits activity against neuroblastomas arising in both Th-MYCN and Th-MYCN/ALKmice, revealed in situ using MRI. Native Tis an early, sensitive and clinically translatable imaging biomarker of effective treatment response in neuroblastoma.

Overview

  • The study assessed the efficacy of cabozantinib against high-risk neuroblastoma tumours in GEM models using multiparametric MRI.
  • The study investigated the activity of cabozantinib against tumours arising in both MYCN-amplified and ALK-mutated neuroblastoma mice.
  • The primary objective of the study was to evaluate the tumour growth delay and survival benefit in response to cabozantinib treatment in neuroblastoma models.

Comparative Analysis & Findings

  • Cabozantinib treatment caused significant growth delay in tumours in both Th-MYCN and Th-MYCN/ALK mice, with a 24-48% reduction in tumour volume.
  • Significant reductions in native T, R*, and ADC were observed in cabozantinib-treated tumours, indicating tumour response to therapy.
  • Histological analysis revealed increased tumour necrosis, apoptosis, and reduced Ki67, CD34, and VEGFR2 staining in cabozantinib-treated tumours, indicating effective treatment response.

Implications and Future Directions

  • The study's findings support the potential of cabozantinib as a treatment option for high-risk neuroblastoma patients.
  • Future studies should investigate the optimal dosing regimen and duration of cabozantinib treatment in neuroblastoma patients.
  • The study's use of native T as an early, sensitive, and clinically translatable imaging biomarker for treatment response has implications for future clinical trials and patient treatment monitoring.
Read Full Article