Department of Medical Oncology, Hospital and Clinical Pharmacy, and Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Clin Cancer Res. 2012 Nov 15;18(22):6306-14. doi: 10.1158/1078-0432.CCR-12-0406. Epub 2012 Sep 26.
The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with (89)Zr-bevacizumab.
The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780(luc+) ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer (89)Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo (89)Zr-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry.
Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered (89)Zr-bevacizumab tumor uptake by 21.7% ± 4.0% [mean standardized uptake value (SUV(mean)) 2.3 ± 0.2 vs. 2.9 ± 0.2, P < 0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 ± 0.8%ID/g vs. 14.0 ± 1.7%ID/g, P < 0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P < 0.01).
Tumor VEGF-A levels are decreased by everolimus. (89)Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy.
mTOR 通路在卵巢癌中经常被激活。mTOR 抑制剂，如依维莫司，可以减少癌细胞中 VEGF-A 的产生。我们研究了早期依维莫司治疗是否可以通过正电子发射断层扫描（PET）用（89）Zr-贝伐珠单抗来监测。
在一系列人卵巢癌细胞系和皮下接种 A2780（luc+）卵巢癌细胞的 BALB/c 小鼠中，确定了依维莫司对 VEGF-A 分泌的影响。小鼠每天腹腔内（i.p.）给予 10mg/kg 依维莫司 14 天。在治疗前后进行了（89）Zr 标记的贝伐珠单抗的 PET 扫描。进行了（89）Zr-贝伐珠单抗的离体生物分布和相关组织分析。用 ELISA 法测量肿瘤 VEGF-A 水平，用免疫组化法测定平均血管密度（MVD）。
依维莫司治疗降低了所有细胞系上清液中的 VEGF-A 水平。依维莫司使（89）Zr-贝伐珠单抗肿瘤摄取降低了 21.7%±4.0%[标准化摄取值（SUV(mean)）2.3±0.2 与 2.9±0.2，P<0.01]。离体生物分布也显示治疗组与对照组动物肿瘤中的示踪剂摄取较低（7.8±0.8%ID/g 与 14.0±1.7%ID/g，P<0.01），而其他组织无差异。这与肿瘤裂解物中治疗组与未治疗组的 VEGF-A 蛋白水平降低（P=0.04）和 MVD 降低（P<0.01）一致。
依维莫司降低了肿瘤 VEGF-A 水平。（89）Zr-贝伐珠单抗 PET 可用于监测肿瘤 VEGF-A 水平，作为 mTOR 抑制剂治疗抗血管生成作用的早期生物标志物。
