Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis

The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therap...

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Main Authors: Yunzhou Shi, Jason Oeh, Anna Hitz, Maj Hedehus, Jeffrey Eastham-Anderson, Franklin V. Peale, Jr., Patricia Hamilton, Thomas O'Brien, Deepak Sampath, Richard A.D. Carano
Format: Article
Language:English
Published: Elsevier 2017-11-01
Series:Neoplasia: An International Journal for Oncology Research
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558617303251
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author Yunzhou Shi
Jason Oeh
Anna Hitz
Maj Hedehus
Jeffrey Eastham-Anderson
Franklin V. Peale, Jr.
Patricia Hamilton
Thomas O'Brien
Deepak Sampath
Richard A.D. Carano
author_facet Yunzhou Shi
Jason Oeh
Anna Hitz
Maj Hedehus
Jeffrey Eastham-Anderson
Franklin V. Peale, Jr.
Patricia Hamilton
Thomas O'Brien
Deepak Sampath
Richard A.D. Carano
author_sort Yunzhou Shi
collection DOAJ
description The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS) 19F–MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF) to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ), which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B20.4.1.1) was found by MS 19F–MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients.
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spelling doaj.art-1b96baaaac2f4413aedd350f7287303d2022-12-21T17:31:53ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022017-11-01191195095910.1016/j.neo.2017.07.010Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral AnalysisYunzhou Shi0Jason Oeh1Anna Hitz2Maj Hedehus3Jeffrey Eastham-Anderson4Franklin V. Peale, Jr.5Patricia Hamilton6Thomas O'Brien7Deepak Sampath8Richard A.D. Carano9Department of Biomedical Imaging, Genentech Inc., South San Francisco, CADepartment of Translational Oncology, Genentech Inc., South San Francisco, CADepartment of Translational Oncology, Genentech Inc., South San Francisco, CADepartment of Biomedical Imaging, Genentech Inc., South San Francisco, CADepartment of Pathology, Genentech Inc., South San Francisco, CADepartment of Pathology, Genentech Inc., South San Francisco, CADepartment of Translational Oncology, Genentech Inc., South San Francisco, CADepartment of Translational Oncology, Genentech Inc., South San Francisco, CADepartment of Translational Oncology, Genentech Inc., South San Francisco, CADepartment of Biomedical Imaging, Genentech Inc., South San Francisco, CAThe effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS) 19F–MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF) to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ), which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B20.4.1.1) was found by MS 19F–MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients.http://www.sciencedirect.com/science/article/pii/S1476558617303251
spellingShingle Yunzhou Shi
Jason Oeh
Anna Hitz
Maj Hedehus
Jeffrey Eastham-Anderson
Franklin V. Peale, Jr.
Patricia Hamilton
Thomas O'Brien
Deepak Sampath
Richard A.D. Carano
Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis
Neoplasia: An International Journal for Oncology Research
title Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis
title_full Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis
title_fullStr Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis
title_full_unstemmed Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis
title_short Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis
title_sort monitoring and targeting anti vegf induced hypoxia within the viable tumor by 19f mri and multispectral analysis
url http://www.sciencedirect.com/science/article/pii/S1476558617303251
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