Intravital imaging to monitor therapeutic response in moving hypoxic regions resistant to PI3K pathway targeting in pancreatic cancer

Conway, J. R.W. et al. (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. (doi: 10.1016/j.celrep.2018.05.038) (PMID:29898401) (PMCID:PMC6019737)

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: Articles
• Additional Information: This work was supported by an NHMRC Project Grant, an NHMRC Fellowship, an NBCF Innovator Grant, an ARC Future Fellowship, a Len Ainsworth Pancreatic Cancer Fellowship, Cancer Council NSW Grant, a Tour de Cure Grant, and CRUK core funding (A17196 and A21139). This project was made possible by an Avner Pancreatic Cancer Foundation Grant.
• Keywords: AZD2014, Akt, FRET, PI3K pathway, PLIM, hypoxia, intravital imaging, nanoparticles, pancreatic cancer, pro-drug.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Timpson, Dr Paul and Morton, Professor Jen and Sansom, Professor Owen
• Authors: Conway, J. R.W., Warren, S. C., Herrmann, D., Murphy, K. J., Cazet, A. S., Vennin, C., Shearer, R. F., Killen, M. J., Magenau, A., Mélénec, P., Pinese, M., Nobis, M., Zaratzian, A., Boulghourjian, A., Da Silva, A. M., Del Monte-Nieto, G., Adam, A. S.A., Harvey, R. P., Haigh, J. J., Wang, Y., Croucher, D. R., Sansom, O. J., Pajic, M., Caldon, C. E., Morton, J. P., and Timpson, P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 13 June 2018
• Copyright Holders: Copyright © 2018 Crown Copyright
• First Published: First published in Cell Reports 23(11): 3312-3326
• Publisher Policy: Reproduced under a Creative Commons License