Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale (LIB), AP-HP, Hôpital Beaujon, Paris, France.
Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale (LIB), Paris, France.
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033819886896. doi: 10.1177/1533033819886896.
Association of drugs acting against different antiangiogenic mechanisms may increase therapeutic effect and reduce resistance. Noninvasive monitoring of changes in the antiangiogenic response of individual tumors could guide selection and administration of drug combinations. Noninvasive detection of early therapeutic response during dual, vertical targeting of the vascular endothelial growth factor pathway was investigated in an ectopic subcutaneous xenograft model for human pancreatic tumor.
Dynamic contrast-enhanced ultrasound 12 MHz was used to monitor tumor-bearing Naval Medical Research Institute mice beginning 15 days after tumor implantation. Mice received therapy from 15 to 29 days with sorafenib (N = 9), ziv-aflibercept (N = 11), combined antiangiogenic agents (N = 11), and placebo control (N = 14). Sorafenib (BAY 43-9006; Nexavar), a multikinase inhibitor acting on Raf kinase and receptor tyrosine kinases-including vascular endothelial growth factor receptors 2 and 3-was administered daily (60 mg/kg, per os). Ziv-aflibercept (ZALTRAP), a high-affinity ligand trap blocking the activity of vascular endothelial growth factor A, vascular endothelial growth factor B, and placental growth factor was administered twice per week (40 mg/kg, intraperitoneally).
Functional evaluation with dynamic contrast-enhanced ultrasound indicated stable tumor vascularization for the control group while revealing significant and sustained reduction after 1 day of therapy in the combined group ( = .007). There was no survival benefit or penalty due to drug combination. The functional progression-free survival assessed with dynamic contrast-enhanced ultrasound was significantly higher for the 3 treated groups; whereas, the progression-free survival based on tumor size did not discriminate therapeutic effect.
Dynamic contrast-enhanced ultrasound, therefore, presents strong potential to monitor microvascular modifications during antiangiogenic therapy, a key role to monitoring antiangiogenic combining therapy to adapt dose range drug.
针对不同抗血管生成机制的药物联合应用可能会提高疗效，减少耐药性。对个体肿瘤抗血管生成反应的变化进行非侵入性监测，可以指导药物组合的选择和给药。本研究在人胰腺肿瘤异位皮下移植瘤模型中，对血管内皮生长因子通路的双靶点、垂直靶向治疗早期治疗反应的非侵入性检测进行了研究。
从肿瘤植入后 15 天开始，使用 12MHz 动态对比增强超声监测携带肿瘤的海军医学研究所小鼠。从第 15 天到第 29 天，9 只小鼠接受索拉非尼（sorafenib，Nexavar）治疗（BAY 43-9006，60mg/kg，口服），11 只小鼠接受 ziv-aflibercept（ZALTRAP，40mg/kg，腹腔内注射）治疗，11 只小鼠接受联合抗血管生成药物治疗，14 只小鼠接受安慰剂对照治疗。Ziv-aflibercept 是一种高亲和力的配体陷阱，可阻断血管内皮生长因子 A、血管内皮生长因子 B 和胎盘生长因子的活性。
动态对比增强超声功能评估显示，对照组肿瘤血管化稳定，而联合组在治疗后 1 天即显示出显著且持续的降低（=0.007）。药物联合并未带来生存获益或惩罚。基于动态对比增强超声评估的功能无进展生存期在 3 个治疗组中明显较高；而基于肿瘤大小评估的无进展生存期则不能区分治疗效果。
因此，动态对比增强超声具有监测抗血管生成治疗期间微血管变化的巨大潜力，这是监测抗血管生成联合治疗以适应药物剂量范围的关键作用。
