Toll-like receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis

• Published in: British journal of cancer 2013-04, Vol.108 (8), p.1616-1623
• Main Authors: Damiano, V, Rosa, R, Formisano, L, Nappi, L, Gelardi, T, Marciano, R, Cozzolino, I, Troncone, G, Agrawal, S, Veneziani, B M, De Placido, S, Bianco, R, Tortora, G
• Format: Article
• Language: English
• Subjects: 692/699/67/1059/602; 692/699/67/2328; 692/699/67/589/1588/1351; Angiogenesis; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; Cells; Drug dosages; Drug Resistance; Drug Synergism; Epidemiology; Epidermal growth factor; Everolimus; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Hypoxia; Kidney cancer; Kidney Neoplasms - blood supply; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Kinases; Medical sciences; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Nephrology. Urinary tract diseases; Oligonucleotides - genetics; Oligonucleotides - immunology; Oligonucleotides - pharmacology; Oncology; Random Allocation; Signal transduction; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - genetics; Translational Therapeutics; Tumors; Tumors of the urinary system; Vascular endothelial growth factor; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.153

Background: Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors. Methods: We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau ( VHL ) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells. Results: Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions. Conclusion: A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.