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Induction and Testing of Hypoxia in Cell Culture
07:01

Induction and Testing of Hypoxia in Cell Culture

Published on: August 12, 2011

Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

George V Thomas1, Chris Tran, Ingo K Mellinghoff

  • 1Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.

Nature Medicine
|December 13, 2005
PubMed

Insights

Loss of the Von Hippel-Lindau (VHL) gene sensitizes kidney cancer to mTOR inhibitors. This occurs by blocking hypoxia-inducible factor (HIF1A) translation, suggesting VHL as a biomarker for mTOR therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mammalian target of rapamycin (mTOR) inhibitors show variable efficacy in cancer treatment.
  • The role of Von Hippel-Lindau (VHL) tumor suppressor gene loss in cancer therapy response is unclear.

Purpose of the Study:

  • To investigate the impact of VHL gene loss on kidney cancer sensitivity to mTOR inhibitors.
  • To explore the underlying molecular mechanisms and potential imaging biomarkers.

Main Methods:

  • In vitro and in vivo (mouse models) studies using kidney cancer cells with VHL deficiency.
  • Assessment of CCI-779 (mTOR inhibitor) effects on cell growth and protein translation.
  • Analysis of hypoxia-inducible factor 1-alpha (HIF1A) mRNA translation and VHL-resistant HIF1A expression.
  • Positron emission tomography (PET) imaging using fluorodeoxyglucose (FDG) in VHL-deficient tumors.

Main Results:

  • VHL-deficient kidney cancer cells exhibit increased sensitivity to the mTOR inhibitor CCI-779.
  • CCI-779 treatment blocks HIF1A mRNA translation, leading to growth arrest.
  • This growth arrest is reversed by expressing a VHL-resistant HIF1A.
  • VHL-deficient tumors display enhanced FDG uptake, dependent on mTOR activity.

Conclusions:

  • Loss of VHL function sensitizes kidney cancer to mTOR inhibitors.
  • HIF1A translation is a key mediator of this sensitivity.
  • FDG-PET may serve as a pharmacodynamic biomarker for mTOR inhibitor therapy in VHL-deficient kidney cancer.

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