Vascular disruption in combination with mTOR inhibition in renal cell carcinoma

Leigh Ellis, Preeti Shah, Hans Hammers, Kristin Lehet, Paula Sotomayor, Gissou Azabdaftari, Mukund Seshadri, Roberto Pili

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)383-392
Number of pages10
JournalMolecular cancer therapeutics
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Vascular disruption in combination with mTOR inhibition in renal cell carcinoma'. Together they form a unique fingerprint.

  • Cite this

    Ellis, L., Shah, P., Hammers, H., Lehet, K., Sotomayor, P., Azabdaftari, G., Seshadri, M., & Pili, R. (2012). Vascular disruption in combination with mTOR inhibition in renal cell carcinoma. Molecular cancer therapeutics, 11(2), 383-392. https://doi.org/10.1158/1535-7163.MCT-11-0748