Duke biomedical engineers are developing a two-pronged approach to treating pancreatic cancer

Duke biomedical engineers are developing a two-pronged approach to treating pancreatic cancer

Biomedical engineers at Duke University have demonstrated the most effective treatment for pancreatic cancer ever demonstrated in mouse models. While most mouse experiments consider simply stopping growth to be a success, the new treatment completely eliminated tumors in 80% of mice in several model types, including those considered the most difficult to treat.

The approach combines traditional chemotherapy drugs with a new method of irradiating the tumor. Instead of delivering radiation from an external beam that travels through healthy tissue, the treatment implants radioactive iodine-131 directly into the tumor in a gel-like depot that protects healthy tissue and is absorbed by the body after the radiation has worn off.

The results appear online October 19 in the journal Nature Biomedical Engineering.

“We studied over 1,100 treatments in preclinical models and never found results where the tumors shrank and disappeared like we did,” said Jeff Schaal, who conducted the research during his doctoral work in the laboratory of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. “If the rest of the literature says that what we see isn’t happening, then we knew we had something extremely interesting.”

Although pancreatic cancer accounts for only 3.2% of all cancer cases, it is the third leading cause of cancer-related death. It is very difficult to treat because its tumors tend to develop aggressive genetic mutations that make it resistant to many drugs, and it is typically diagnosed very late, when it has already spread to other places in the body.

The current leading treatment combines chemotherapy, which keeps cells in a radiosensitive reproductive state for an extended period of time, with a beam of radiation directed at the tumor. However, this approach is ineffective unless a certain radiation threshold reaches the tumor. And despite recent advances in shaping and directing radiation beams, it is very difficult to reach this threshold without risking serious side effects.

Another method researchers have tried is to implant a radioactive sample encased in titanium directly into the tumor. However, because titanium blocks all radiation except gamma rays, which travel far outside the tumor, it can only remain in the body for a short time before damage to surrounding tissue negates its purpose.

“Right now, there just isn't a good way to treat pancreatic cancer,” said Schaal, who is now director of research at Cereius, Inc., a biotechnology startup in Durham, North Carolina, that is working to commercialize targeted radionuclide therapy through a different technology regimen.

To get around these problems, Schaal decided to try a similar implantation method using a substance made from elastin-like polypeptides (ELPs), which are synthetic chains of amino acids bonded together to form a gel-like substance with tailored properties. Because ELPs are a focus of the Chilkoti lab, he and colleagues were able to develop a delivery system well suited to this task.

The ELPs exist in a liquid state at room temperature, but form a stable gel-like substance in the warmer human body. When the ELPs are injected into a tumor along with a radioactive element, they form a small depot that encloses radioactive atoms. In this case, researchers chose to use iodine-131, a radioactive isotope of iodine, because doctors have commonly used it in medical treatments for decades and its biological effects are well known.

The ELP depot surrounds the iodine-131 and prevents it from leaking into the body. The iodine-131 emits beta radiation that penetrates the biogel and releases almost all of its energy into the tumor without reaching the surrounding tissue. Over time, the ELP depot breaks down into its amino acid components and is absorbed by the body -; but not before the iodine-131 has decayed into a harmless form of xenon.

The beta radiation also improves the stability of the ELP biogel. This helps the depot last longer and only collapses when the radiation has been used up.”

Jeff Schaal, Research Director at Cereius, Inc.

In the new work, Schaal and his collaborators in the Chilkoti lab tested the new treatment alongside paclitaxel, a commonly used chemotherapy drug to treat various mouse models of pancreatic cancer. They chose pancreatic cancer because it is notoriously difficult to treat, and hoped to show that their radioactive tumor implant produced synergistic effects with chemotherapy that did not occur with relatively short-lived radiation therapy.

The researchers tested their approach on mice with cancer just under the skin caused by various mutations known to occur in pancreatic cancer. They also tested it on mice with tumors in the pancreas, which are much more difficult to treat.

Overall, testing showed a 100% response rate across all models, with tumors completely eliminated in approximately 80% of cases in three-quarters of models. The tests also revealed no immediately obvious side effects beyond chemotherapy alone.

“We believe that constant radiation allows the drugs to interact more strongly with their effects than external radiation therapy allows,” Schaal said. “This leads us to believe that this approach may actually work better than external beam radiation therapy for many other types of cancer.”

However, the approach is still in early preclinical stages and will not be available for human use in the foreseeable future. The researchers say their next step is large animal studies in which they will need to show that the technique can be performed accurately using existing clinical tools and endoscopy techniques that doctors are already trained in. If successful, they will aim for a phase 1 clinical trial on humans.

“My lab has been working on developing new cancer treatments for nearly 20 years, and this work is perhaps the most exciting we have ever done in terms of its potential impact, since late-stage pancreatic cancer is impossible to treat and is invariably fatal.” " said Chilkoti. "Patients with pancreatic cancer deserve better treatment options than are currently available, and I am committed to bringing this to the clinic."

Source:

Duke University

Reference:

Schaal, JL, et al. (2022) Brachytherapy via a depot of biopolymer-bound 131I synergized with nanoparticle paclitaxel in therapy-resistant pancreatic tumors. Natural biomedical engineering. doi.org/10.1038/s41551-022-00949-4.

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