Tracking pancreatic cancer's moving targets

Researchers at the Garvan Institute of Medical Research have pioneered a new approach to fighting treatment-resistant regions within one of the world’s deadliest cancers.

For the first time, they have monitored these drug-resistant regions in pancreatic tumours as they travel, spread and grow in real time — and are finding new ways to neutralise these moving targets. The results of their work have been published in the journal Cell Reports.

Regions of low oxygen, which move around within tumours, are a hallmark of pancreatic tumours. These travelling pockets of low oxygen are resistant to treatment and a major concern in the fight against pancreatic cancer, according to Associate Professor Paul Timpson.

“Cancer cells are incredibly adaptable,” said Associate Professor Timpson, whose team led the new study. “Depriving them of oxygen makes them more aggressive, more invasive and resistant to radiotherapy, chemotherapy and other cancer treatments.

“And the movement of these low-oxygen, drug-resistant regions in cancer is incredibly problematic, as it means that those areas are constantly changing — it’s here today, there tomorrow, with no way for us to know where the resistance will be in the future.”

To tackle this problem, Associate Professor Timpson and his team developed a live tracking approach that allows them to observe the drug response of these treatment-resistant compartments in pancreatic tumours. They combined high-level imaging technology with oxygen-sensitive nanoparticles that can be read on the order of microseconds, and whose reach extends deep into tumours to reveal oxygen content at a single-cell resolution. In parallel, they are able to overlay this information on oxygen levels with nanosecond readouts of drug performance using fluorescent biosensor technology.

Movement of a low-oxygen compartment in a mouse pancreatic tumour over 24 hours.

The team saw that cells were resistant to three clinically relevant pancreatic cancer treatments, including the cancer inhibitor AZD2014. “We took advantage of a tool that is ideal for this situation — TH-302 — a molecular ‘warhead’ that’s activated only in low-oxygen regions,” explained James Conway, a PhD student in Associate Professor Timpson’s lab and lead author of the study.

Using a combination of TH-302 and AZD2014, the researchers precisely targeted low-oxygen, drug-resistant tumour regions and observed a marked improvement in drug response and inhibition of tumour growth in pancreatic tumour-bearing mice.

“The beauty of this new treatment combination lies in the precision of low oxygen-activated drugs,” said Conway. “Their highly toxic, activated form is triggered specifically in low-oxygen regions. This makes them incredibly versatile — they can be given in highly concentrated doses because their toxicity to normal tissues is minimal, but in low-oxygen areas of the tumour it is lethal, exactly where the drug resistance occurs.”

Conway highlighted the clinical relevance of the study, noting, “AZD2014 is already being used in clinical trials and, given the potential for use in cancer treatment, we want to find combination therapies that will improve patient responses even further beyond the current standard of care. We believe our results bring us one step closer towards application in a clinical setting.”

Beyond pancreatic cancer, the results have the potential to change the wider landscape of cancer treatment. Treatment resistance as a result of low oxygen is a fundamental problem across many cancers, and the findings are likely to have a broad impact in paving the way to more effective, targeted cancer therapies.

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