Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer

Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon...

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Vydané v:	Cell reports (Cambridge) Ročník 23; číslo 11; s. 3312 - 3326
Hlavní autori:	Conway, James R.W., Warren, Sean C., Herrmann, David, Murphy, Kendelle J., Cazet, Aurélie S., Vennin, Claire, Shearer, Robert F., Killen, Monica J., Magenau, Astrid, Mélénec, Pauline, Pinese, Mark, Nobis, Max, Zaratzian, Anaiis, Boulghourjian, Alice, Da Silva, Andrew M., del Monte-Nieto, Gonzalo, Adam, Arne S.A., Harvey, Richard P., Haigh, Jody J., Wang, Yingxiao, Croucher, David R., Sansom, Owen J., Pajic, Marina, Caldon, C. Elizabeth, Morton, Jennifer P., Timpson, Paul
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Elsevier Inc 12.06.2018 Cell Press Elsevier
Predmet:	Akt Animals AZD2014 Benzamides Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Drug Therapy, Combination Female Fluorescence Resonance Energy Transfer FRET Humans Hypoxia intravital imaging Intravital Microscopy - methods Mice Mice, Inbred BALB C Morpholines - pharmacology Morpholines - therapeutic use nanoparticles Nanoparticles - chemistry Nitroimidazoles - pharmacology Nitroimidazoles - therapeutic use pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Phosphatidylinositol 3-Kinases - metabolism Phosphoramide Mustards - pharmacology Phosphoramide Mustards - therapeutic use PI3K pathway PLIM pro-drug Proto-Oncogene Proteins c-akt - metabolism Pyrimidines Signal Transduction - drug effects Transplantation, Heterologous Tumor Microenvironment hypoxia pancreatic cancer AZD2014 nanoparticles PLIM PI3K pathway FRET Akt intravital imaging pro-drug
ISSN:	2211-1247, 2211-1247
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Abstract	Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. [Display omitted] •Hypoxia presents a moving pocket of resistance in pancreatic ductal adenocarcinoma.•Dual intravital imaging allows live tracking of drug response in hypoxic regions.•Combination with a hypoxia-activated pro-drug alleviates resistance.•This has implications for combatting resistance in a broad range of therapies. Intravital imaging facilitates the real-time tracking and targeting of moving hypoxic regions within pancreatic ductal adenocarcinoma. Using this approach, Conway et al. alleviate hypoxia-induced resistance to a dual mTORC1/2 inhibitor AZD2014, improving PI3K pathway inhibition and demonstrating a powerful dual imaging modality applicable to targeting other pathways and cancers.
AbstractList	Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302.Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. : Intravital imaging facilitates the real-time tracking and targeting of moving hypoxic regions within pancreatic ductal adenocarcinoma. Using this approach, Conway et al. alleviate hypoxia-induced resistance to a dual mTORC1/2 inhibitor AZD2014, improving PI3K pathway inhibition and demonstrating a powerful dual imaging modality applicable to targeting other pathways and cancers. Keywords: pancreatic cancer, intravital imaging, hypoxia, FRET, pro-drug, PI3K pathway, nanoparticles, PLIM, Akt, AZD2014 Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. [Display omitted] •Hypoxia presents a moving pocket of resistance in pancreatic ductal adenocarcinoma.•Dual intravital imaging allows live tracking of drug response in hypoxic regions.•Combination with a hypoxia-activated pro-drug alleviates resistance.•This has implications for combatting resistance in a broad range of therapies. Intravital imaging facilitates the real-time tracking and targeting of moving hypoxic regions within pancreatic ductal adenocarcinoma. Using this approach, Conway et al. alleviate hypoxia-induced resistance to a dual mTORC1/2 inhibitor AZD2014, improving PI3K pathway inhibition and demonstrating a powerful dual imaging modality applicable to targeting other pathways and cancers. Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor. To overlay this microenvironmental information with drug response, we applied a FRET biosensor for Akt activity, which is a key effector of the PI3K pathway. Performing dual intravital imaging of drug response in different tumor compartments, we demonstrate an improved drug response to a combination therapy using the dual mTORC1/2 inhibitor AZD2014 with the hypoxia-activated pro-drug TH-302. • Hypoxia presents a moving pocket of resistance in pancreatic ductal adenocarcinoma. • Dual intravital imaging allows live tracking of drug response in hypoxic regions. • Combination with a hypoxia-activated pro-drug alleviates resistance. • This has implications for combatting resistance in a broad range of therapies. Intravital imaging facilitates the real-time tracking and targeting of moving hypoxic regions within pancreatic ductal adenocarcinoma. Using this approach, Conway et al. alleviate hypoxia-induced resistance to a dual mTORC1/2 inhibitor AZD2014, improving PI3K pathway inhibition and demonstrating a powerful dual imaging modality applicable to targeting other pathways and cancers.
Author	Nobis, Max Zaratzian, Anaiis Wang, Yingxiao Boulghourjian, Alice Magenau, Astrid Conway, James R.W. Warren, Sean C. Da Silva, Andrew M. Vennin, Claire Mélénec, Pauline Pajic, Marina Shearer, Robert F. Pinese, Mark Timpson, Paul Killen, Monica J. Murphy, Kendelle J. del Monte-Nieto, Gonzalo Morton, Jennifer P. Adam, Arne S.A. Herrmann, David Haigh, Jody J. Croucher, David R. Sansom, Owen J. Harvey, Richard P. Cazet, Aurélie S. Caldon, C. Elizabeth
AuthorAffiliation	3 Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia 9 Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK 2 St Vincent’s Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia 8 Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK 5 Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia 7 School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland 6 Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA 1 Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia 4 School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2033, Australia
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Copyright	2018 Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved. Crown Copyright © 2018 Published by Elsevier Inc. All rights reserved. 2018
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Keywords	hypoxia pancreatic cancer AZD2014 nanoparticles PLIM PI3K pathway FRET Akt intravital imaging pro-drug
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Snippet	Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to...
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SubjectTerms	Akt Animals AZD2014 Benzamides Cell Line, Tumor Drug Resistance, Neoplasm - drug effects Drug Therapy, Combination Female Fluorescence Resonance Energy Transfer FRET Humans Hypoxia intravital imaging Intravital Microscopy - methods Mice Mice, Inbred BALB C Morpholines - pharmacology Morpholines - therapeutic use nanoparticles Nanoparticles - chemistry Nitroimidazoles - pharmacology Nitroimidazoles - therapeutic use pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Phosphatidylinositol 3-Kinases - metabolism Phosphoramide Mustards - pharmacology Phosphoramide Mustards - therapeutic use PI3K pathway PLIM pro-drug Proto-Oncogene Proteins c-akt - metabolism Pyrimidines Signal Transduction - drug effects Transplantation, Heterologous Tumor Microenvironment
Title	Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer
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