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

Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mT... Full description

Journal Title: Nature medicine 2006-01, Vol.12 (1), p.122-127
Main Author: Sawyers, Charles L
Other Authors: Thomas, George V , Tran, Chris , Mellinghoff, Ingo K , Welsbie, Derek S , Chan, Emily , Fueger, Barbara , Czernin, Johannes
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/16341243
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title: Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer
format: Article
creator:
  • Sawyers, Charles L
  • Thomas, George V
  • Tran, Chris
  • Mellinghoff, Ingo K
  • Welsbie, Derek S
  • Chan, Emily
  • Fueger, Barbara
  • Czernin, Johannes
subjects:
  • 5' Untranslated Regions
  • Animals
  • Brain - metabolism
  • Cell Line, Tumor
  • Densitometry
  • DNA - chemistry
  • DNA Primers - chemistry
  • DNA, Complementary - metabolism
  • Fluorodeoxyglucose F18 - pharmacology
  • Glucose - metabolism
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit - physiology
  • Immunoblotting
  • Kidney Neoplasms - metabolism
  • Luciferases - metabolism
  • Mice
  • Neoplasm Transplantation
  • Polymerase Chain Reaction
  • Positron-Emission Tomography
  • Protein Biosynthesis
  • Protein Kinases - metabolism
  • Radiopharmaceuticals - pharmacology
  • RNA, Messenger - metabolism
  • Time Factors
  • TOR Serine-Threonine Kinases
  • Transfection
ispartof: Nature medicine, 2006-01, Vol.12 (1), p.122-127
description: Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5′ untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleHypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer
creatorSawyers, Charles L ; Thomas, George V ; Tran, Chris ; Mellinghoff, Ingo K ; Welsbie, Derek S ; Chan, Emily ; Fueger, Barbara ; Czernin, Johannes
creatorcontribSawyers, Charles L ; Thomas, George V ; Tran, Chris ; Mellinghoff, Ingo K ; Welsbie, Derek S ; Chan, Emily ; Fueger, Barbara ; Czernin, Johannes
descriptionInhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5′ untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.
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subject5' Untranslated Regions ; Animals ; Brain - metabolism ; Cell Line, Tumor ; Densitometry ; DNA - chemistry ; DNA Primers - chemistry ; DNA, Complementary - metabolism ; Fluorodeoxyglucose F18 - pharmacology ; Glucose - metabolism ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit - physiology ; Immunoblotting ; Kidney Neoplasms - metabolism ; Luciferases - metabolism ; Mice ; Neoplasm Transplantation ; Polymerase Chain Reaction ; Positron-Emission Tomography ; Protein Biosynthesis ; Protein Kinases - metabolism ; Radiopharmaceuticals - pharmacology ; RNA, Messenger - metabolism ; Time Factors ; TOR Serine-Threonine Kinases ; Transfection
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abstractInhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5′ untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting.
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pmid16341243
doi10.1038/nm1337
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