Almeida Gilberto S, King Philippa, Hallsworth Albert, Webber Hannah, Popov Sergey, Miranda Susana, Yogev Orli, Pearson Andrew D J, Chesler Louis, Jamin Yann, Robinson Simon P
Division of Radiotherapy & Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom; Division of Clinical Studies, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom.
Division of Clinical Studies, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom.
Neoplasia. 2025 Jul;65:101170. doi: 10.1016/j.neo.2025.101170. Epub 2025 May 12.
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 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.
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.
在神经母细胞瘤中，MYCN基因扩增与血管生成增强及预后不良相关。间变性淋巴瘤激酶（ALK）基因突变可与MYCN基因扩增同时出现，预示预后极差。血管内皮生长因子（VEGF）和肝细胞生长因子（HGF）/c-MET信号传导与神经母细胞瘤进展有关。卡博替尼对VEGFR2和MET具有强大活性。
使用多参数MRI评估卡博替尼对高危神经母细胞瘤GEM模型中肿瘤的疗效。对荷瘤的Th-MYCN和Th-ALK/Th-MYCN小鼠在接受30mg/kg/天卡博替尼或赋形剂治疗前、治疗后24小时和48小时进行成像。评估治疗引起的肿瘤体积、固有T、R*和ADC的变化，并寻找组织学相关性。另外的Th-MYCN小鼠每天接受治疗，最长持续28天。
卡博替尼在Th-MYCN小鼠肿瘤治疗后24小时和48小时分别引起显著的24%和60%的生长延迟，固有T显著降低6%。治疗后48小时肿瘤R*显著降低。从卡博替尼治疗的小鼠中确定肿瘤坏死和凋亡显著增加，而Ki67、CD34和VEGFR2染色显著降低。对Th-ALK/Th-MYCN小鼠的治疗导致肿瘤生长显著延迟4%和21%，48小时时固有T显著降低5%。对Th-MYCN小鼠每天进行卡博替尼治疗在7天内引起显著的肿瘤生长延迟，并转化为显著的生存获益。
卡博替尼对Th-MYCN和Th-MYCN/ALK小鼠中产生的神经母细胞瘤均表现出活性，通过MRI原位显示。固有T是神经母细胞瘤有效治疗反应的早期、敏感且具有临床可转化性的成像生物标志物。
