Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.
Axitinib and crizotinib combination therapy inhibits bone loss in a mouse model of castration resistant prostate cancer.
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DOI：
10.1186/1471-2407-14-742
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发表时间：
2014-10-02
期刊：
影响因子：
3.8
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Eswaraka J;Giddabasappa A;Han G;Lalwani K;Eisele K;Feng Z;Affolter T;Christensen J;Li G
耐阉割前列腺癌(CRPC)是男性癌症相关死亡的主要原因。患者死亡和发病的主要原因是骨转移和骨重塑，导致成骨细胞和溶骨性病变。最近，多激酶抑制剂(VEGFR2和c-MET抑制剂)卡波赞替尼被证明对患者的骨损伤有疗效。在这项研究中，我们在小鼠模型中测试了多种激酶抑制剂：axitinib(VEGFR抑制剂)和crizotinib(c-met抑制剂)。在完整和去势的NOD-SCID-伽马(NSG)小鼠身上种植VCAP-LUC细胞作为皮下植入，以证实雄激素依赖。对于骨转移模型，两组NSG小鼠(去势和完整)在左侧胫骨骨髓腔内原位注射VCaP-Luc细胞。每周使用生物发光成像监测小鼠的肿瘤生长情况。根据肿瘤生物发光信号将动物随机分为4组：赋形剂组、单用Crizotinib组、单用axitinib组、Crizotinib+axitinib组。动物每周进行活体二维X射线成像，以监测骨重建。研究结束时，动物被安乐死，取双侧胫骨进行体外高分辨率三维微型计算机断层扫描(μCT)成像。皮下模型显示雄激素刺激对VCaP-Luc细胞的生长可能有帮助，但不是必需的。在完整动物的胫骨内生长的VCap-Luc细胞引起广泛的骨重建，伴有成骨(骨形成)和骨溶解(骨基质溶解)混合病变。成骨细胞病变占主导地位，有时从胫骨骨干延伸到周围组织。相比之下，在整个研究过程中，只有溶骨性病变在去势动物身上表现突出。单独使用Crizotinib治疗可减少去势动物的溶骨性损害。单用阿西替尼可以减少完好动物的成骨细胞损伤。阿昔替尼和克里佐替尼联合治疗可显着抑制VCaP-Luc细胞的胫骨改建，使成骨和溶骨损伤明显减轻。我们的数据表明，联合抑制c-met和VEGFR可有益于治疗CRPC的转移性骨疾病，并且这两种药物作用于疾病的两个不同阶段。本文的在线版本(DOI：10.1186/1471-2407-14-742)包含补充材料，可供授权用户使用。
Castration resistant prostate cancer (CRPC) is a leading cause of cancer-related deaths in men. The primary cause of mortality and morbidity in patients is bone metastases and remodeling resulting in osteoblastic and osteolytic lesions. Recently, cabozantinib, a multi-kinase inhibitor (VEGFR2 and c-MET inhibitor), was shown to have efficacy on bone lesions in patients. In this study we tested multi-kinase inhibitors: axitinib (VEGFR inhibitor) and crizotinib (c-MET inhibitor) in a combination trial in mice models. VCaP-Luc cells were grown as subcutaneous implants in intact and castrated NOD-SCID-gamma (NSG) mice to confirm the androgen dependency. For bone metastasis model two cohorts of NSG mice (castrated and intact) received orthotopic injection of VCaP-Luc cells into the bone marrow cavity of left tibia. Mice were monitored weekly for tumor growth using bioluminescence imaging. Animals were randomized into 4 groups based on the tumor bioluminescence signal: vehicle, crizotinib alone, axitinib alone, crizotinib and axitinib in combination. Animals were imaged weekly by in vivo 2-D X-ray imaging to monitor bone remodeling. At the end of the study animals were euthanized and both tibias were extracted for ex vivo high-resolution 3-D micro-computed tomography (μCT) imaging. Subcutaneous model showed that androgen stimulation may be helpful but not essential for the growth of VCaP-Luc cells. VCaP-Luc cells grown intra-tibially in intact animals caused extensive remodeling of bone with mixed osteoblastic (bone formation) and osteolytic (bone matrix dissolution) lesions. The osteoblastic lesions were predominant and at times extended beyond the tibial shaft into the surrounding tissue. In contrast, only osteolytic lesions were prominent throughout the study in castrated animals. Treatment with crizotinib alone reduced the osteolytic lesions in castrated animals. Axitinib alone reduced the osteoblastic lesions in the intact animals. Combination therapy with axitinib and crizotinib remarkably inhibited the tibial remodeling by VCaP-Luc cells which resulted in a significant reduction of both osteoblastic and osteolytic lesions. Our data show that combined inhibition of c-MET and VEGFR can be beneficial for treatment of metastatic bone disease in CRPC and that the drugs act on two different stages of the disease. The online version of this article (doi:10.1186/1471-2407-14-742) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
Attard, G;Sarker, D;Reid, A;Molife, R;Parker, C;de Bono, J S
通讯作者：
de Bono, J S
影响因子：
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