Receptor tyrosine kinase inhibitors have shown clinical benefit in clear cell renal cell carcinoma (ccRCC), but novel therapeutic strategies are needed. The angiopoietin/Tie2 and MET pathways have been implicated in tumor angiogenesis, metastases, and macrophage infiltration. In our study, we used trebananib, an angiopoietin 1/2 inhibitor, and a novel small-molecule MET kinase inhibitor in patient-derived xenograft (PDX) models of ccRCC. Our goal was to assess the ability of these compounds to alter the status of tumor-infiltrating macrophages, inhibit tumor growth and metastases, and prolong survival. Seven-week-old SCID mice were implanted subcutaneously or orthotopically with human ccRCC models. One month postimplantation, mice were treated with angiopoietin 1/2 inhibitor trebananib (AMG 386), MET kinase inhibitor, or combination. In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone, and in combination with a MET kinase inhibitor, significantly reduced lung metastases and M2 macrophage infiltration (P = 0.0075 and P = 0.0205, respectively). Survival studies revealed that treatment of the orthotopically implanted RP-R-02LM tumors yielded a significant increase in survival in both trebananib and combination groups. In addition, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared with vehicle and both single-agent groups. Our results show that the combination of trebananib with a MET kinase inhibitor significantly inhibits the spread of metastases, reduces infiltrating M2-type macrophages, and prolongs survival in our highly metastatic ccRCC PDX model, suggesting a potential use for this combination therapy in treating patients with ccRCC.

中文翻译：

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血管生成素-TIE2 和 MET 的双重抑制改变肿瘤微环境并延长肾细胞癌转移模型的生存期

受体酪氨酸激酶抑制剂已在透明细胞肾细胞癌 (ccRCC) 中显示出临床益处，但需要新的治疗策略。血管生成素/Tie2 和 MET 通路与肿瘤血管生成、转移和巨噬细胞浸润有关。在我们的研究中，我们在 ccRCC 的患者来源异种移植 (PDX) 模型中使用了 trebananib、血管生成素 1/2 抑制剂和新型小分子 MET 激酶抑制剂。我们的目标是评估这些化合物改变肿瘤浸润巨噬细胞状态、抑制肿瘤生长和转移以及延长生存期的能力。七周大的 SCID 小鼠皮下或原位植入人类 ccRCC 模型。植入后 1 个月，小鼠接受血管生成素 1/2 抑制剂 trebananib (AMG 386)、MET 激酶抑制剂或组合治疗。在我们的转移性 ccRCC PDX 模型中，RP-R-02LM、单独使用 trebananib 以及与 MET 激酶抑制剂联合使用可显着减少肺转移和 M2 巨噬细胞浸润（分别为 P = 0.0075 和 P = 0.0205）。生存研究表明，原位植入的 RP-R-02LM 肿瘤的治疗使 trebananib 和组合组的生存率显着增加。此外，与载体和两个单药组相比，皮下植入的原发肿瘤的切除使联合组具有显着的生存优势。我们的结果表明，trebananib 与 MET 激酶抑制剂的组合显着抑制转移的扩散，减少浸润的 M2 型巨噬细胞，并延长我们高度转移的 ccRCC PDX 模型的存活率，