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Modeling Spontaneous Metastatic Renal Cell Carcinoma (mRCC) in Mice Following Nephrectomy
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Vascular disruption in combination with mTOR inhibition in renal cell carcinoma

Leigh Ellis1, Preeti Shah, Hans Hammers

  • 1Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.

Molecular Cancer Therapeutics
|November 16, 2011
PubMed

Insights

Combining ASA404, a tumor-vascular disrupting agent (tumor-VDA), with everolimus enhanced anti-cancer effects in renal cell carcinoma (RCC) models. This combination therapy showed significant tumor reduction and vascular damage, warranting further investigation for RCC treatment.

Area of Science:

  • Oncology
  • Vascular Biology
  • Pharmacology

Background:

  • Renal cell carcinoma (RCC) is a malignancy driven by angiogenesis and hypoxia.
  • Antiangiogenic agents are of interest for RCC management.
  • The efficacy of tumor-vascular disrupting agents (tumor-VDA) in RCC is underexplored.

Purpose of the Study:

  • To investigate the therapeutic efficacy of combining the tumor-VDA ASA404 with the mTOR inhibitor everolimus against RCC.
  • To evaluate the combination's effects on tumor vascularization and growth in preclinical models.

Main Methods:

  • In vitro studies using endothelial cells.
  • In vivo studies with orthotopic RENCA tumors and RCC xenografts.
  • Magnetic resonance imaging (MRI) to assess vascular response.
  • Tumor growth measurements and histopathologic evaluation.

Main Results:

  • Combination therapy enhanced inhibition of endothelial cell sprouting.
  • ASA404 increased vascular permeability early post-treatment.
  • Combination treatment significantly reduced tumor blood volume and induced marked vascular damage.
  • Histology revealed extensive necrosis and reduced viable tumor rim with combination therapy.

Conclusions:

  • Combining tumor-VDA ASA404 with mTOR inhibitor everolimus demonstrates significant therapeutic potential in preclinical RCC models.
  • This novel combination strategy warrants further investigation for RCC treatment.
  • The combination effectively targets tumor vasculature and induces tumor cell death.

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