Dual inhibition of angiopoietin-TIE2 and MET alters the tumor microenvironment and prolongs survival in a metastatic model of renal cell carcinoma

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 post implantation, 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. Additionally, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared to 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.