Biomedical engineers at Duke University have come up with an innovative new approach for delivering radiochemotherapy that claims to be the most effective treatment for pancreatic cancer ever recorded. The paper, published in Nature, details the results of a pre-clinical study showing that tumours were eliminated in 80% of the mouse models analysed.
Implantation impasse
Pancreatic cancer might only account for 3.2% of all cancer cases, but this devastating disease is notoriously difficult to treat. It is often only detected once the cancer has metastasised to other areas of the body and is resistant to many forms of treatment. In fact, despite its low prevalence, it is the third-leading cause of all cancer-related deaths.
The current treatment for pancreatic cancer involves a combination of chemotherapy and radiation. However, locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy approaches unless a certain threshold of radiation reaches the site of the tumour – and this is difficult to achieve without adverse side effects. Other approaches have looked at using implantation (where radioactive elements are delivered directly to tumours) to fight the disease, but the titanium encasings used so far can only remain in the body for short periods before causing unintended damage.
To overcome these challenges, Ashutosh Chilkoti (Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke) and his lab turned to special heat-reactive polypeptides.
Gelling with cancer
Instead of delivering radiation via an external beam that travels through healthy tissue, the team used an implant of radioactive iodine-131 (covered in protective gel) that is deposited directly into tumours. This process protects any healthy tissues from the harmful effects of radiation and the implant is absorbed by the body once the iodine-131 has decayed.
The unique part of their new approach is the gel-like substance encasing the implant and preventing the radiation from leaking into surrounding tissues. This substance is made of thermally responsive elastin-like polypeptides (synthetic chains of amino acids bonded together) that exist in a liquid state at room temperature but turn to a stable gel once inside the human body.
“We did a deep dive through over 1100 treatments across preclinical models and never found results where the tumours shrank away and disappeared like ours did,” said Jeff Schaal, who conducted the research during his PhD in the laboratory of Chilkoti. “When the rest of the literature is saying that what we’re seeing doesn’t happen, that’s when we knew we had something extremely interesting.”
The promise of pancreatic treatment
To test their approach, they looked at how the treatment performed in various mouse models of pancreatic cancer. Some of these mice has cancers just under their skin (created by several different mutations known to occur in pancreatic cancer) and some had tumours within the pancreas, which is much more difficult to treat.
Overall, they recorded a 100% response rate across all models, with the tumours being completely eliminated in three-quarters of the models about 80% of the time. The tests also revealed no immediately obvious side effects beyond what is caused by chemotherapy alone.
As for a mechanism, histological analysis revealed that the new approach led to changes in the expression of intracellular collagen and junctional proteins within the TME thought to correlate with the improved delivery and accumulation of the chemotherapy drug within the tumour.
“We think the constant radiation allows the drugs to interact with its effects more strongly than external beam therapy allows,” Schaal said. “That makes us think that this approach might actually work better than external beam therapy for many other cancers, too.”
Though it won’t be available for human use any time soon, the results are promising. The next step for the team is larger animal studies and eventually a Phase 1 clinical trial.
“My lab has been working on developing new cancer treatments for close to 20 years, and this work is perhaps the most exciting we have done in terms of its potential impact, as late-stage pancreatic cancer is impossible to treat and is invariably fatal,” said Chilkoti. “Pancreatic cancer patients deserve better treatment options than are currently available, and I am deeply committed to taking this all the way into the clinic.”
