Vascular disruption in combination with mTOR inhibition in renal cell carcinoma

• Published in: Molecular cancer therapeutics 2012-02, Vol.11 (2), p.383-392
• Main Authors: Ellis, Leigh, Shah, Preeti, Hammers, Hans, Lehet, Kristin, Sotomayor, Paula, Azabdaftari, Gissou, Seshadri, Mukund, Pili, Roberto
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Animals; Antigens - metabolism; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Everolimus; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Immunohistochemistry; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - prevention & control; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Proteoglycans - metabolism; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Tumor Burden - drug effects; Xanthones - administration & dosage; Xanthones - pharmacology; Xenograft Model Antitumor Assays - methods
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0748

Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted.