Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.
Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.
- 2013
Available online from MWHC library: 1995 - present (after 1 year), Available in print through MWHC library: 1999 - February 2003
CONCLUSIONS: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. 2013 AACR. EXPERIMENTAL DESIGN: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression 130224s induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. PURPOSE: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. RESULTS: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies.
English
1078-0432
*Angiogenesis Inhibitors/tu [Therapeutic Use]
*Antineoplastic Agents/tu [Therapeutic Use]
*Neoplasms/dt [Drug Therapy]
*Neoplasms/me [Metabolism]
*Signal Transduction/de [Drug Effects]
*Vascular Endothelial Growth Factor A/ai [Antagonists & Inhibitors]
*Vascular Endothelial Growth Factor A/me [Metabolism]
Angiogenesis Inhibitors/pd [Pharmacology]
Animals
Antibodies, Monoclonal, Humanized/pd [Pharmacology]
Antibodies, Monoclonal, Humanized/tu [Therapeutic Use]
Antineoplastic Agents/pd [Pharmacology]
Disease Models, Animal
Drug Evaluation, Preclinical
Gene Expression Profiling
Gene Expression Regulation, Neoplastic/de [Drug Effects]
Humans
Mice
Neoplasms/ge [Genetics]
Neoplasms/mo [Mortality]
Neovascularization, Pathologic/dt [Drug Therapy]
Neovascularization, Pathologic/ge [Genetics]
Neovascularization, Pathologic/me [Metabolism]
Neuroendocrine Tumors/dt [Drug Therapy]
Neuroendocrine Tumors/ge [Genetics]
Neuroendocrine Tumors/me [Metabolism]
Pancreatic Neoplasms/dt [Drug Therapy]
Pancreatic Neoplasms/ge [Genetics]
Pancreatic Neoplasms/me [Metabolism]
Tumor Markers, Biological/ge [Genetics]
Tumor Markers, Biological/me [Metabolism]
Washington Cancer Institute
Journal Article
Available online from MWHC library: 1995 - present (after 1 year), Available in print through MWHC library: 1999 - February 2003
CONCLUSIONS: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. 2013 AACR. EXPERIMENTAL DESIGN: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression 130224s induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy. PURPOSE: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. RESULTS: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies.
English
1078-0432
*Angiogenesis Inhibitors/tu [Therapeutic Use]
*Antineoplastic Agents/tu [Therapeutic Use]
*Neoplasms/dt [Drug Therapy]
*Neoplasms/me [Metabolism]
*Signal Transduction/de [Drug Effects]
*Vascular Endothelial Growth Factor A/ai [Antagonists & Inhibitors]
*Vascular Endothelial Growth Factor A/me [Metabolism]
Angiogenesis Inhibitors/pd [Pharmacology]
Animals
Antibodies, Monoclonal, Humanized/pd [Pharmacology]
Antibodies, Monoclonal, Humanized/tu [Therapeutic Use]
Antineoplastic Agents/pd [Pharmacology]
Disease Models, Animal
Drug Evaluation, Preclinical
Gene Expression Profiling
Gene Expression Regulation, Neoplastic/de [Drug Effects]
Humans
Mice
Neoplasms/ge [Genetics]
Neoplasms/mo [Mortality]
Neovascularization, Pathologic/dt [Drug Therapy]
Neovascularization, Pathologic/ge [Genetics]
Neovascularization, Pathologic/me [Metabolism]
Neuroendocrine Tumors/dt [Drug Therapy]
Neuroendocrine Tumors/ge [Genetics]
Neuroendocrine Tumors/me [Metabolism]
Pancreatic Neoplasms/dt [Drug Therapy]
Pancreatic Neoplasms/ge [Genetics]
Pancreatic Neoplasms/me [Metabolism]
Tumor Markers, Biological/ge [Genetics]
Tumor Markers, Biological/me [Metabolism]
Washington Cancer Institute
Journal Article