Conway, James R W and Warren, Sean C and Herrmann, David and Murphy, Kendelle J and Cazet, Aurélie S and Vennin, Claire and Shearer, Robert F and Killen, Monica J and Magenau, Astrid and Mélénec, Pauline and Pinese, Mark and Nobis, Max and Zaratzian, Anaiis and Boulghourjian, Alice and Da Silva, Andrew M and del Monte-Nieto, Gonzalo and Adam, Arne S A and Harvey, Richard P and Haigh, Jody J and Wang, Yingxiao and Croucher, David R and Sansom, Owen J and Pajic, Marina and Caldon, C Elizabeth and Morton, Jennifer P and Timpson, Paul (2018) Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer. Cell Reports, 23 (11). pp.3312-3326. ISSN 22111247 (Gold OA)
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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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 17 Jun 2018 23:37 |
| Last Modified: | 17 Jun 2018 23:41 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/734 |
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