Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma

  • Mol Cancer Ther. 2020 Jan;19(1):147-156. doi: 10.1158/1535-7163.MCT-18-1202.
May Elbanna  #  1 ,  Ashley R Orillion  #  1  2 ,  Nur P Damayanti  1 ,  Remi Adelaiye-Ogala  1  3 ,  Li Shen  4 ,  Kiersten Marie Miles  5 ,  Sreenivasulu Chintala  1 ,  Eric Ciamporcero  6 ,  Swathi Ramakrishnan  3 ,  Sheng-Yu Ku  3 ,  Karen Rex  7 ,  Sean Caenepeel  7 ,  Angela Coxon  7 ,  Roberto Pili  8
Affiliations
  • 1. Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana.
  • 2. Department of Cellular and Molecular Biology, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York.
  • 3. Department of Cancer Pathology and Prevention, University at Buffalo, Roswell Park Cancer Institute, Buffalo, New York.
  • 4. Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.
  • 5. Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York.
  • 6. Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
  • 7. Oncology Research, Amgen Inc., Thousand Oaks, California.
  • 8. Genitourinary Cancers Program, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana. [email protected].
  • # Contributed equally.
PMID: 31582532 DOI: 10.1158/1535-7163.MCT-18-1202
Abstract

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.

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