Biomedical engineers at Duke University have demonstrated the most effective treatment for pancreatic cancer ever recorded in mouse models. While most mouse trials consider simply halting growth a success, the new treatment completely eliminated tumors in 80 percent of mice across several model types, including those considered the most difficult to treat.
The approach combines traditional
chemotherapy drugs with a new method for irradiating the tumor. Rather than
delivering radiation from an external beam that travels through healthy tissue,
the treatment implants radioactive iodine-131 directly into the tumor within a
gel-like depot that protects healthy tissue and is absorbed by the body after
the radiation fades away.
The results appear online October 19 in
the journal Nature Biomedical Engineering.
“We did a deep dive through over 1,100
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 study 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.”
Despite accounting for only 3.2 percent
of all cancer cases, pancreatic cancer 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 sites
in the body.
The current leading treatment combines
chemotherapy, which keeps cells in a stage of reproduction vulnerable to
radiation for longer periods of time, with a beam of radiation targeted at the
tumor. This approach, however, is ineffective unless a certain threshold of
radiation reaches the tumor. And despite recent advances in shaping and
targeting radiation beams, that threshold is very difficult to reach without
risking severe side effects.
Another method researchers have tried
involves implanting a radioactive sample encased in titanium directly within
the tumor. But because titanium blocks all radiation other than gamma rays,
which travel far outside the tumor, it can only remain within the body for a
short period of time before damage to surrounding tissue begins to defeat the
purpose.
“There’s just no good way to treat pancreatic
cancer right now,” said Schaal, who is now director of research at Cereius, a
Durham, NC, biotechnology startup working to commercialize a targeted
radionuclide therapy through a different technology scheme.
To skirt these issues, Schaal decided to
try a similar implantation method using a substance made of 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 was able to work with colleagues to design a delivery
system well-suited for the task.
The ELPs exist in a liquid state at room
temperature but form a stable gel-like substance within the warmer human body.
When injected into a tumor along with a radioactive element, the ELPs form a
small depot encasing radioactive atoms. In this case, the researchers decided
to use iodine-131, a radioactive isotope of iodine, because doctors have used
it widely in medical treatments for decades and its biological effects are well
understood.
The ELP depot encases the iodine-131 and
prevents it from leaking out into the body. The iodine-131 emits beta
radiation, which penetrates the biogel and deposits almost all its energy into
the tumor without reaching the surrounding tissue. Over time, the ELP depot
degrades into its constituent amino acids 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,” Schaal said. “That helps the depot last longer
and only break down after the radiation is spent.”
In the new paper, Schaal and his
collaborators in the Chilkoti laboratory tested the new treatment in concert
with paclitaxel, a commonly used chemotherapy drug, to treat various mouse
models of pancreatic cancer. They chose pancreatic cancer because of its infamy
for being difficult to treat, hoping to show that their radioactive tumor
implant creates synergistic effects with chemotherapy that relatively
short-lived radiation beam therapy does not.
The researchers tested their approach on
mice with cancers just under their skin created by several different mutations
known to occur in pancreatic cancer. They also tested it on mice that had
tumors within the pancreas, which is much more difficult to treat.
Overall, the tests saw a 100 percent
response rate across all models, with the tumors 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.
“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.”
The approach, however, is still in its
early preclinical stages and will not be available for human use anytime soon.
The researchers say their next step is large animal trials, where they will
need to show that the technique can be accurately done with the existing
clinical tools and endoscopy techniques that doctors are already trained on. If
successful, they look toward a Phase 1 clinical trial in humans.
“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,” Chilkoti said. “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.”
Source: https://pratt.d
uke.edu/about/news/radioactive-tumor-implant
Journal article: https://www.nature.com/articles/s41551-022-00949-4
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