Kratzsch Tobias, Piffko Andras, Broggini Thomas, Czabanka Marcus, Vajkoczy Peter
Department of Neurosurgery, Charité University Hospital, Berlin, Germany.
Department of Physics, University of California, San Diego, La Jolla, CA, United States.
Front Oncol. 2020 Feb 19;10:174. doi: 10.3389/fonc.2020.00174. eCollection 2020.
Spinal metastatic disease remains a major problem of oncological diseases. Patients affected may suffer pain, spinal instability, and severe neurological deficits. Today, palliative surgery and radiotherapy are the mainstays of therapy. In contrast, preventive treatment strategies or treatment concepts for an early stage are lacking. Here, we have used a syngeneic, experimental spine metastases model in the mouse to test the efficacy of mTOR inhibition and anti-angiogenesis on the formation and progression of spinal melanoma metastases. We used our previously established syngeneic spinal metastases mouse model by injecting luciferin-transfected B16 melanoma cells into the common carotid artery. Following injection, mice were treated with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) complex, axitinib, a tyrosine kinase inhibitor, that blocks vascular endothelial growth factor receptors (VEGFR) 1-3, as well as placebo. Animals were followed-up daily by neurological assessment and by repeat bioluminescence imaging. With occurrence of neurological deficits, a spinal MRI was performed, and mice were sacrificed. The whole spine was dissected free and analyzed by immunohistochemical techniques. Overall survival was 23 days in the control group, significantly prolonged to 30 days ( = 0.04) in the everolimus group, and to 28 days ( = 0.04) in the axitinib group. While 78% of mice in the placebo group developed symptomatic metastatic epidural spinal cord compression, only 50% did so in the treatment groups. The mean time to manifestation of paralysis was 22 days in the control group, 26 days ( = 0.10) in the everolimus group, and 27 days ( = 0.06) in the axitinib group. Screening for spinal metastases by bioluminescence imaging on two different time points showed a decrease in metastatic tumor formation in the treatment groups compared to the controls. Immunohistochemical analysis confirmed the bioactivity of the two compounds: The Ki67 proliferation labeling index was reduced in the everolimus group and numbers of CD31 positive endothelial cells were reduced in the axitinib group. Both, the mTOR inhibitor everolimus as well as antiangiogenetic effects by the VEGFR inhibitor axitinib showed potential to prevent and retard formation of symptomatic spinal metastases. However, the therapeutic efficacy was only mild in this experimental model.
脊柱转移性疾病仍然是肿瘤疾病的一个主要问题。受影响的患者可能会遭受疼痛、脊柱不稳定和严重的神经功能缺损。如今，姑息性手术和放疗是主要的治疗方法。相比之下，缺乏针对早期阶段的预防性治疗策略或治疗理念。在此，我们利用小鼠的同基因实验性脊柱转移模型来测试mTOR抑制和抗血管生成对脊柱黑色素瘤转移形成和进展的疗效。我们通过将荧光素转染的B16黑色素瘤细胞注入颈总动脉，使用我们先前建立的同基因脊柱转移小鼠模型。注射后，小鼠分别接受依维莫司（一种雷帕霉素哺乳动物靶点（mTOR）复合物抑制剂）、阿昔替尼（一种酪氨酸激酶抑制剂，可阻断血管内皮生长因子受体（VEGFR）1 - 3）以及安慰剂治疗。每天通过神经学评估和重复生物发光成像对动物进行随访。出现神经功能缺损时，进行脊柱MRI检查，并对小鼠实施安乐死。将整个脊柱分离出来，通过免疫组织化学技术进行分析。对照组的总生存期为23天，依维莫司组显著延长至30天（P = 0.04），阿昔替尼组延长至28天（P = 0.04）。安慰剂组78%的小鼠出现有症状的转移性硬膜外脊髓压迫，而治疗组只有50%出现。对照组出现瘫痪的平均时间为22天，依维莫司组为26天（P = 0.10），阿昔替尼组为27天（P = 0.06）。在两个不同时间点通过生物发光成像筛查脊柱转移显示，与对照组相比，治疗组转移性肿瘤形成减少。免疫组织化学分析证实了这两种化合物的生物活性：依维莫司组的Ki67增殖标记指数降低，阿昔替尼组CD31阳性内皮细胞数量减少。mTOR抑制剂依维莫司以及VEGFR抑制剂阿昔替尼的抗血管生成作用均显示出预防和延缓有症状脊柱转移形成的潜力。然而，在这个实验模型中治疗效果仅为轻度。
