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

• DOI: 10.1016/j.celrep.2018.05.038
• Publication Date: 2018-06-14T00:30:00Z
• Authors: James R.W. Conway; Sean C. Warren; David Herrmann; Kendelle J. Murphy; Aurélie S. Cazet; Claire Vennin; Robert F. Shearer; Monica J. Killen; Astrid Magenau; Pauline Mélénec; Mark Pinese; Max Nobis; Anaiis Zaratzian; Alice Boulghourjian; Andrew M. Da Silva; Gonzalo del Monte...; Arne S.A. Adam; Richard P. Harvey; Jody J. Haigh; Yingxiao Wang; David R. Croucher; Owen J. Sansom; Marina Pajic; C. Elizabeth Caldon; Jennifer P. Morton; Paul Timpson
• Keywords: Hypoxia; Tumor Hypoxia; Intravital microscopy

Application of advanced intravital imaging facilitates dynamic monitoring pathway activity upon therapeutic inhibition. Here, we assess resistance to inhibition the PI3K within hypoxic microenvironment pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced is observed for three clinically relevant inhibitors. To address this clinical problem, have mapped tumor hypoxia by both immunofluorescence phosphorescence lifetime oxygen-sensitive nanoparticles demonstrate that these regions move transiently around tumor. overlay microenvironmental information with drug response, applied FRET biosensor Akt activity, which key effector pathway. Performing dual response in different compartments, an improved combination therapy using mTORC1/2 inhibitor AZD2014 hypoxia-activated pro-drug TH-302.