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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)147-156
Number of pages10
JournalMolecular cancer therapeutics
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2020

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Angiopoietins
Tumor Microenvironment
Renal Cell Carcinoma
Survival
Phosphotransferases
Macrophages
Heterografts
Angiopoietin-2
Angiopoietin-1
Neoplasm Metastasis
Neoplasms
SCID Mice
Receptor Protein-Tyrosine Kinases
trebananib
Therapeutics
Lung
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma. / Elbanna, May; Orillion, Ashley R.; Damayanti, Nur P.; Adelaiye-Ogala, Remi; Shen, Li; Miles, Kiersten Marie; Chintala, Sreenivasulu; Ciamporcero, Eric; Ramakrishnan, Swathi; Ku, Sheng Yu; Rex, Karen; Caenepeel, Sean; Coxon, Angela; Pili, Roberto.

In: Molecular cancer therapeutics, Vol. 19, No. 1, 01.01.2020, p. 147-156.

Research output: Contribution to journalArticle

Elbanna, M, Orillion, AR, Damayanti, NP, Adelaiye-Ogala, R, Shen, L, Miles, KM, Chintala, S, Ciamporcero, E, Ramakrishnan, S, Ku, SY, 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, vol. 19, no. 1, pp. 147-156. https://doi.org/10.1158/1535-7163.MCT-18-1202
Elbanna, May ; Orillion, Ashley R. ; Damayanti, Nur P. ; Adelaiye-Ogala, Remi ; Shen, Li ; Miles, Kiersten Marie ; Chintala, Sreenivasulu ; Ciamporcero, Eric ; Ramakrishnan, Swathi ; Ku, Sheng Yu ; Rex, Karen ; Caenepeel, Sean ; Coxon, Angela ; Pili, Roberto. / Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma. In: Molecular cancer therapeutics. 2020 ; Vol. 19, No. 1. pp. 147-156.
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AU - Damayanti, Nur P.

AU - Adelaiye-Ogala, Remi

AU - Shen, Li

AU - Miles, Kiersten Marie

AU - Chintala, Sreenivasulu

AU - Ciamporcero, Eric

AU - Ramakrishnan, Swathi

AU - Ku, Sheng Yu

AU - Rex, Karen

AU - Caenepeel, Sean

AU - Coxon, Angela

AU - Pili, Roberto

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