Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.
Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.
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DOI：
10.1158/1078-0432.ccr-14-2031
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发表时间：
2015-04-15
期刊：
影响因子：
--
通讯作者：
Bhatt RS
中科院分区：
文献类型：
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作者：
Zhang L;Wang X;Bullock AJ;Callea M;Shah H;Song J;Moreno K;Visentin B;Deutschman D;Alsop DC;Atkins MB;Mier JW;Signoretti S;Bhasin M;Sabbadini RA;Bhatt RS
VEGFR 2酪氨酸激酶抑制（TKI）是转移性RCC患者的一种有价值的治疗方法。然而，对治疗的抵抗是不可避免的。新靶点的确定可能会为TKI初治或耐药RCC患者带来更好的治疗。在这项研究中，我们在小鼠模型中对VEGFR TKI耐药肿瘤进行了转录组分析，发现SPHK/S1 P通路在耐药时上调。我们在两种RCC小鼠异种移植模型中使用抗S1 P mAb（sphingomab）测试了S1 P通路抑制，并评估了转移性RCC患者的肿瘤SPHK表达和S1 P血浆水平。耐药肿瘤表达几个缺氧调节基因。SPHK 1途径是伴随VEGFR TKI治疗耐药的最高度上调的途径之一。SPHK 1在人肾细胞癌中表达，SPHK 1活性产物S1 P在转移性肾细胞癌患者中升高，表明人肾细胞癌的行为可能部分是由于S1 P的过度产生。在两种小鼠模型中，Sphingomab对细胞外S1 P的中和作用减缓了肿瘤生长。对舒尼替尼治疗产生耐药性的荷瘤小鼠也表现出sphingomab对肿瘤生长的抑制作用。通过MRI测量，Sphingomab治疗导致肿瘤血流量减少。我们的研究结果表明，S1 P抑制可能是初治RCC患者以及对VEGFR TKI治疗耐药的患者的一种新的治疗策略。
VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic RCC. However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for both patients with TKI naïve or resistant RCC. In this study, we performed transcriptome analysis of VEGFR TKI resistant tumors in a murine model and discovered that the SPHK/S1P pathway is upregulated at the time of resistance. We tested S1P pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Resistant tumors expressed several hypoxia regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC suggesting that human RCC behavior could, in part, be due to over-production of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment naïve RCC and also in the setting of resistance to VEGFR TKI therapy.