Scientists at the Garvan Institute of Medical Research imaged live drug response and resistant “pockets’ in pancreatic cancer. The scientists developed a tool that allowed them to observe live microscopy footage of a key cancer driver molecule that is often overly active in pancreatic cancer, and could be used to reveal new paths to tackling drug resistance with combination therapies.
The findings are published in Science Advances.
“Aberrant AKT activation occurs in a number of cancers, metabolic syndromes, and immune disorders, making it an important target for the treatment of many diseases,” wrote the researchers. “To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models.”
“The AKT pathway has been a target for therapy for decades but drugs targeting this pathway alone have thus far been largely ineffective in the clinic,” said Paul Timpson, PhD, head of the invasion & metastasis lab, co-lead of the cancer ecosystems program at Garvan, and co-senior author of the study.
The new imaging model will help the researchers see a clear way for how combination approaches could reduce drug resistance and switch off AKT to help stop tumors from growing and spreading.
“Using intravital microscopy at the ACRF INCITe Centre to image our biosensor model, we blocked AKT activity using clinical treatments, but could see, in real-time, that AKT remained switched on inside drug-resistant pockets, specifically in areas close to invasive borders or with low oxygen supply,” said co-senior author Max Nobis, PhD, head of the Intravital Imaging Expertise Center at the VIB-KU Leuven Center for Cancer Biology and visiting scientist at Garvan.
“We also saw that as cancer cells got closer to a blood vessel, AKT started to activate. This indicates that AKT not only drives cancer growth, but it also actively drives the early events of cancer spread to other sites around the body. For the first time, we’re able to see these events in a live pancreas.”
The researchers will next use the biosensor model to optimize new combination therapies with AKT pathway inhibitors for pancreatic cancer and other AKT-driven cancers.
