Dual inhibition of angiopoietin-Tie2 and MET alters the tumor microenvironment and prolongs survival in a metastatic model of renal cell carcinoma

May Elbanna, Ashley R. Orillion, Nur P. Damayanti, Remi Adelaiye-Ogala, Li Shen, Kiersten Marie Miles, Sreenivasulu Chintala, Eric Ciamporcero, Swathi Ramakrishnan, Sheng yu Ku, Karen Rex, Sean Caenepeel, Angela Coxon, Roberto Pili

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3 Scopus citations

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 ¼ 0.0075 and P ¼ 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.

Original languageEnglish (US)
Pages (from-to)147-156
Number of pages10
JournalMolecular cancer therapeutics
Volume19
Issue number1
DOIs
StatePublished - 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Elbanna, M., Orillion, A. R., Damayanti, N. P., Adelaiye-Ogala, R., Shen, L., Miles, K. M., Chintala, S., Ciamporcero, E., Ramakrishnan, S., Ku, S. Y., Rex, K., Caenepeel, S., Coxon, A., & Pili, R. (2020). Dual inhibition of angiopoietin-Tie2 and MET alters the tumor microenvironment and prolongs survival in a metastatic model of renal cell carcinoma. Molecular cancer therapeutics, 19(1), 147-156. https://doi.org/10.1158/1535-7163.MCT-18-1202