Format

Send to

Choose Destination
Cell Rep. 2018 Jun 12;23(11):3312-3326. doi: 10.1016/j.celrep.2018.05.038.

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

Author information

1
Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia.
2
Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia.
3
St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
4
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
5
St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia; School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, NSW 2033, Australia.
6
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
7
Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA.
8
Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia; School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
9
Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
10
Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. Electronic address: j.morton@beatson.gla.ac.uk.
11
Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Cancer Division, Sydney, NSW 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia. Electronic address: p.timpson@garvan.org.au.

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.

KEYWORDS:

AZD2014; Akt; FRET; PI3K pathway; PLIM; hypoxia; intravital imaging; nanoparticles; pancreatic cancer; pro-drug

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center