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

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.

Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer

“…Both Wu et al, 2016 andSrivastava et al, 2014 suggest that certain postoperative treatment combinations involving anti-Ang2 agents may be worthy of future clinical trial evaluation (Srivastava et al, 2014;Wu et al, 2016a). Additionally, a recent study reported perioperative neoadjuvant plus adjuvant treatment of trebananib in an ectopic PDX model of renal cell carcinoma (Elbanna et al, 2020). In this case, mice were treated with trebananib before resection of subcutaneous primary tumors and treatment was continued postsurgery; this strategy resulted in prolonged survival and reduced lung metastasis and both effects were enhanced when the drug was combined with a MET-targeted TKI.…”

A renal cell carcinoma tumorgraft platform to advance precision medicine

“…RCC TGs reproduce the histology, gene expression, DNA copy number alterations, and mutations of the corresponding tumors from affected individuals ( Sivanand et al, 2012 ; Pavía-Jiménez et al, 2014 ; Grisanzio et al, 2011 ). In addition, RCC TGs preserve the drug responsiveness of human RCC ( Sivanand et al, 2012 ; Chen et al, 2016b ; Karam et al, 2011 ; Ingels et al, 2014 ; Cho et al, 2016 ; Zhao et al, 2017 ; Elbanna et al, 2020 ; Moserle et al, 2020 ). In studies optimizing drug administration regimens to model human exposures, RCC TGs have been shown to respond to sunitinib ( Motzer et al, 2009 ; Bukowski et al, 2007 ), but not to erlotinib, used as a negative control ( Sivanand et al, 2012 ).…”

Improving antitumor immunity using antiangiogenic agents: Mechanistic insights, current progress, and clinical challenges

“…In the tumor microenvironment, VEGF promotes the proliferation and function of immunosuppressive cells and dampens cytotoxic function of CTLs by promoting the expression of inhibitory molecules. Abbreviations are as follows: CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCL, CXC-chemokine ligand; DC, dendritic cells; FASL, FAS antigen ligand; MHC; major histocompatibility complex; HPC, hematopoietic progenitor cell; LAG3, lymphocyte activation gene 3 protein; MDSC, myeloid-derived suppressive cells; PD-L1, programmed death-ligand 1; TIM3, T cell immunoglobulin mucin receptor 3; TME, tumor microenvironment; Treg cell, regulatory T cell; VEGF, vascular endothelial growth factor TA B L E 1 Immunomodulatory effects of antiangiogenic treatments in preclinical and translational studies The presence of TAMs in the tumor microenvironment↓ [30] Abbreviations: Ang, angiopoietin; APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; NA, not applicable; TAM, tumor-associated macrophage; IFN, interferon; VEGF, vascular endothelial growth factor.…”

“…While effective antiangiogenic treatments have well‐established efficacies in halting tumor growth, under certain conditions, they cannot eradicate tumors via monotherapy due to compensatory mechanisms [ 18 ]. Hence, combining antiangiogenic agents with other therapeutic strategies might be necessary for effective tumor eradication [ 26 , 27 , 28 , 29 , 30 , 31 ]; among these strategies, targeting the VEGF/VEGFR axis has been the most common combination treatment modality in 2020 [ 16 ].…”