Abstract
SummaryApplication 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.
Highlights
A recurring feature in malignant cancers is the aggressive alterations that cells undergo in order to survive in a low-oxygen environment
We assess resistance to therapeutic inhibition of the phosphatidylinositol 3-kinase (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 Forster resonance energy transfer (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
Summary
A recurring feature in malignant cancers is the aggressive alterations that cells undergo in order to survive in a low-oxygen (hypoxic) environment. Hypoxiaactivated pro-drugs (HAPs) provide an efficient method to deliver cytotoxic agents to hypoxic tumor regions, diminishing the off-target effects from conventional smallmolecule therapeutics (O’Connor et al, 2016; Wilson and Hay, 2011). These HAPs may affect normoxic tumor regions by virtue of a local bystander effect and in this way provide an even more versatile approach for targeted delivery (Abbattista et al, 2015; Sun et al, 2015). HAPs are generally insufficient for use as monotherapies, and current clinical trials focus on their application in combination with chemotherapeutics, radiotherapy, or targeted therapies (Borad et al, 2015; Van Cutsem et al, 2016; Wilson and Hay, 2011)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
