Researchers have successfully tested a new treatment approach against pancreatic cancer in animal experiments. They implanted a gel-like, radioactive implant directly into the tumor in mice. In combination with chemotherapy, the radiation inside the tumor caused this normally stubborn type of cancer to disappear completely in five out of six mice. If further animal experiments also bring positive results, the researchers are aiming for clinical studies on humans.
Pancreatic cancer is one of the most aggressive and difficult to treat types of cancer. Although pancreatic tumors account for only 3.2 percent of all cancer cases, they are the third leading cause of cancer-related death. One reason is that the tumors are prone to genetic mutations that make them resistant to many drugs. In addition, they are often recognized too late, so that metastases have already formed. The current standard of care combines chemotherapy, which keeps the tumor cells in a state susceptible to radiation, with radiation therapy. However, the difficulty lies in delivering a sufficiently high dose of radiation to the tumor without causing serious side effects.
irradiation from within
A new approach is therefore to implant radioactive material directly into the tumor so that the radiation does not first have to penetrate many layers of healthy tissue. However, previous attempts had a crucial problem: To prevent the radioactive material from spreading in the body after implantation, it was enclosed in titanium. However, this metal is only permeable to gamma radiation, which also spreads far beyond the tumor and damages the surrounding tissue. Corresponding implants can therefore only remain in the body for a short time before the damage outweighs the benefit.
"There's just no good way to treat pancreatic cancer right now," says Jeffrey Schaal of Duke University in Durham. Together with his team, he may have found a solution to this problem: instead of titanium, the researchers used a substance made from so-called elastin-like polypeptides (ELPs). These are synthetic chains of amino acids that are liquid at room temperature but combine with the heat of the body to form a stable gel.
Gel as a depot for radioactive material
Schaal and his colleagues embedded radioactive atoms in this gel – in this case iodine-131, a radioactive isotope that has been used in medicine for decades. The iodine-131 emits beta radiation that penetrates the biogel and reaches the tumor. There, the radiation is almost completely absorbed, so that the surrounding tissue is protected. The gel, in turn, holds the radioactive iodine in place. Over time, it breaks down into its individual amino acids and is broken down by the body—but only after the radioactive material has broken down into a harmless form. "The beta radiation also improves the stability of the ELP biogel," explains Schaal. "This helps the depot to last longer and only deplete when the radiation is used up."
To test the effectiveness of their new approach, the researchers used different mouse models. First, they planted tumors under the skin of mice that carried the mutations typical of pancreatic cancer. On the other hand, in another group of mice, they produced tumors directly in the pancreas, where they are more difficult to treat due to their location in the middle of the body. They implanted the newly developed radioactive gel implant into the tumor of some of the mice and additionally treated them with the chemotherapeutic agent paclitaxel. Other groups of mice received either the implant only, chemotherapy only, or no treatment.
tumors regressed
"The chemotherapy alone showed a minimal effect," the researchers report. "Only one in six mice responded partially." While untreated mice survived around 21.5 days, mice in the chemotherapy group lived an average of 25 days. The radioactive implant alone extended median survival to 38 days and inhibited tumor growth. However, the combination was the most effective: "We observed a significant regression of the tumor in all mice treated in this way, and in five out of six animals the tumor even regressed completely," say the researchers. On average, the animals survived 100.5 days.
"We think that the constant irradiation allows the drugs to interact with the effects of the irradiation more than is possible with external beam radiation therapy," explains Schaal. "This leads us to suspect that this approach could also work better than external radiation therapy for many other types of cancer." Apart from the side effects of chemotherapy, they observed no additional side effects in the mice treated with the new approach.
application in humans is still a long way off
It is still unclear at this stage whether and when the method can be used in clinical practice. In the next step, Schaal and his colleagues want to carry out further animal experiments in which they investigate to what extent the new method can be carried out with existing clinical instruments and techniques. If these tests are also successful, the researchers are aiming for the first clinical studies on humans.
Source: Jeffrey Schaal (Duke University, Durham, USA) et al., Nature Biomedical Engineering, doi: 10.1038/s41551-022-00949-4