In a pioneering study, researchers at the Garvan Institute of Medical Research have discovered a new approach to fight treatment-resistant regions within pancreatic cancer—one of the world’s deadliest cancers. For the first time, they have monitored these drug-resistant regions in pancreatic tumors as they travel, spread, and grow in real time—and are finding new ways to neutralize these moving targets.

The findings, which were uncovered in mice, are published today in Cell Reports.

Pancreatic cancer has one of the poorest survival rates of all cancers, and is predicted to be the second-leading cause of cancer deaths by 2030. The 5-year survival rate stands at less than 7.7%, and has scarcely changed in decades.

Regions of low oxygen, which move around within tumors, are a hallmark of pancreatic tumors. Importantly, these traveling pockets of low oxygen are resistant to treatment. Associate Professor Paul Timpson (Cancer Invasion & Metastasis lab head, Garvan), whose team led the study, says these nomadic regions are a major concern in the fight against pancreatic cancer.

“Cancer cells are incredibly adaptable,” says Timpson. “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, Timpson and his team have overcome a major technical hurdle and developed an innovative live tracking approach, allowing them to observe the drug response of these treatment-resistant compartments in pancreatic tumors.

“To make real gains in the fight against pancreatic cancer,” says Timpson, “we can’t wait for new technology to come to us; instead, we often have to develop it ourselves.”

Using their new, live tracking technology, they monitored individual cells within low-oxygen regions of pancreatic tumors, and observed the response to treatment. They saw that cells were resistant to three clinically relevant pancreatic cancer treatments, including the cancer inhibitor AZD2014.

So how do you attack a resistant, moving target?

For James Conway—a PhD student in Timpson’s lab and the lead author in this study—the answer lies in precision weaponry. “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.”

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

The results from this new study represent an exciting new opportunity for pancreatic cancer, where little progress has been made in the past 40 years.

“The beauty of this new treatment combination lies in the precision of low–oxygen-activated drugs,” says James. “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 tumor it is lethal, exactly where the drug resistance occurs.”

The new findings would not have been possible without new technology developed at Garvan. For Timpson, investing in new technology is key to furthering scientific discovery.

“Instead of static snapshots,” says Timpson “we have a dynamic new way to measure responses in single cells in their native environment—by peering into a live animal. That real-time feedback is incredibly valuable.”

Co-corresponding author Dr. Jennifer Morton, of the Beatson Institute for Cancer Research UK, is optimistic about what these results mean for patients.

“Pancreatic cancer is a devastating disease with virtually no effective treatments—but our live imaging showed us that although these areas can move around, we can target them and hopefully reverse resistance to therapy, increasing the options for these patients.”

Looking ahead, James highlights the clinical relevance of this study.

“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, these 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 these findings are likely to have a broad impact in paving the way to more effective, targeted cancer therapies.