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

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-Nieto, Arne S.A. Adam, Richard P. Harvey, Jody J. Haigh, Yingxiao WangDavid R. Croucher, Owen J. Sansom, Marina Pajic, C. Elizabeth Caldon, Jennifer P. Morton, Paul Timpson

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21 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)3312-3326
Number of pages15
JournalCell Reports
Volume23
Issue number11
DOIs
Publication statusPublished - 12 Jun 2018

Keywords

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

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