Most effective treatment for pancreatic cancer in mouse models ever recorded

Science -- October 25, 2022: In 80% of mice across several models, internal radiation and chemotherapy dissolve tumors.
In mice models, biomedical engineers at Duke University have shown the most successful pancreatic cancer treatment ever documented.

The novel medication totally cleared tumors in 80% of mice across various model types, including those thought to be the most challenging to treat, whereas conventional mouse trials consider simply halting growth to be a success.

In this treatment, conventional chemotherapy medications are combined with a novel technique for irradiating the tumor. The treatment implants radioactive iodine-131 directly into the tumor within a gel-like depot that shields healthy tissue and is absorbed by the body once the radiation fades, as opposed to administering radiation from an external beam that passes through healthy tissue.

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

"We did a deep dive through over 1100 treatments across preclinical models and never found results where the tumors shrank away and disappeared like ours did," said Jeff Schaal, who conducted the research during his PhD in the laboratory of Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke. "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."

Pancreatic cancer is the third biggest cause of cancer-related death while only making up 3.2% of all cancer cases. It is highly challenging to treat since it usually spreads to other parts of the body by the time it is discovered, and because its tumors have a propensity to aggressive genetic alterations that render them treatment resistant.

The most effective treatment now available combines radiation directed at the tumor with chemotherapy, which prolongs the time that cells are exposed to radiation while they are in a stage of reproduction. However, this strategy is useless unless a specific amount of radiation penetrates the tumor. And despite recent improvements in the shaping and targeting of radiation beams, it is very challenging to cross that barrier without running the danger of serious side effects.

Another approach that researchers have tried is to implant a titanium-encased radioactive sample right inside the tumor. However, titanium can only remain inside the body for a few length of time before harm to nearby tissue starts to negate the goal because it absorbs all radiation aside from gamma rays, which travel far outside the tumor. Elastin-like polypeptides (ELPs), which are artificial chains of amino acids bound together to produce a gel-like substance with customized properties, were used by Schaal in an attempt to avoid these problems. The Chilkoti lab focuses on ELPs, therefore he was able to collaborate with colleagues to build a delivery mechanism that was effective for the job.

"There's just no good way to treat pancreatic cancer right now," said Schaal, who is now director of research at Cereius, Inc., a Durham, North Carolina biotechnology startup working to commercialize a targeted radionuclide therapy through a different technology scheme.

While the ELPs are liquid at ambient temperature, they solidify into a stable gel-like substance when they are inside a warm body. The ELPs create a tiny depot that contains radioactive atoms when they are introduced into a tumor together with a radioactive substance. Iodine-131, a radioactive isotope of iodine, has been used extensively in medical treatments for many years, and its biological effects are well known. For this reason, the researchers chose to utilize it.

Iodine-131 is contained by the ELP depot, which stops it from leaking into the body. Beta radiation, which is released by the iodine-131, penetrates the biogel and almost entirely enters the tumor, avoiding the surrounding tissue. Iodine-131 must first degrade into a harmless form of xenon before the ELP store can break down into its individual amino acids and be absorbed by the body. In the latest study, Schaal and his colleagues from the Chilkoti laboratory investigated the new therapy in combination with the widely-used chemotherapy medication paclitaxel to treat various pancreatic cancer animal models. In order to demonstrate that their radioactive tumor implant has synergistic benefits with chemotherapy that comparatively short-lived radiation beam therapy does not, they picked pancreatic cancer because of its reputation for being difficult to treat.

"The beta radiation also improves the stability of the ELP biogel," Schaal said. "That helps the depot last longer and only break down after the radiation is spent."

On mice with skin tumors caused by multiple distinct mutations known to occur in pancreatic cancer, the researchers evaluated their method. Additionally, they tested it on animals with pancreatic tumors, which are far more challenging to cure.

Overall, all models in the experiments demonstrated a 100% response rate, with the tumors being totally eradicated in around 80% of the models. Additionally, the testing found no additional immediately noticeable side effects to those brought on by chemotherapy alone.

However, the method is still in the early preclinical phases and won't be ready for human use for a while. The next phase, according to the researchers, will be large animal tests, where they will have to demonstrate that the approach can be carried out accurately using the clinical equipment now in use and the endoscopy methods that doctors have previously received training in. If successful, they plan to conduct a human Phase 1 clinical trial.

"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."

WNCTIMES by Marjorie Farrington

This research was supported by the National Institutes of Health (5R01EB000188) and the National Cancer Institute (R35CA197616).
 

Materials provided by Duke University. Original written by Ken Kingery.

Source Info"
Duke University. "Gel-like, radioactive tumor implant obliterates pancreatic cancer in mice: Combination of internal radiation and chemotherapy dissolves tumors in 80% of mice across multiple models." ScienceDaily. ScienceDaily, 20 October 2022. .



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