Pancreatic cancer is notoriously hard to treat, and researchers at the University of Miami Miller School of Medicine say they may have found a way to strip back some of the tumor’s built-in protection.
In a new preclinical study published in JCI Insight, researchers found that blocking IL1RAP disrupted an inflammatory network that helps pancreatic tumors survive treatment. The work was led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, and is now moving toward a neoadjuvant clinical trial in patients with operable pancreatic cancer before surgery.
The planned trial will combine IL1RAP targeted therapy with chemoimmunotherapy.
Researchers said one of the main reasons pancreatic cancer is so hard to treat is the tumor microenvironment, the community of cells and structural tissue surrounding a tumor that can help cancer survive and resist therapy.
In the study, Jashodeep Datta, M.D., and colleagues described IL1RAP as a receptor that helps link tumor cells, immune cells and fibroblasts into a coordinated system that supports resistance to treatment.
“When we target IL1RAP, we are blocking a shared ‘helper’ receptor that many inflammatory signals rely on to transmit their message,” said Datta, a pancreatic and hepatobiliary surgical oncologist, co-leader of the Gastrointestinal Site Disease Group at Sylvester, and senior author of the study.
The researchers said pancreatic tumors depend heavily on neighboring cells that help them adapt, grow and withstand therapy. Because IL1RAP acts as a shared control point for multiple inflammatory signals, blocking it may interfere with a broader tumor-supporting network.
The study said pancreatic tumors often create an environment that is highly inflamed while also suppressing the immune system. Researchers said this “inflamed but immune-suppressed” state is one reason chemotherapy and immunotherapy can be less effective.
In preclinical studies, the Sylvester team found that inhibiting IL1RAP changed the tumor microenvironment in several ways. Immune-suppressive cells became less abundant, T cells became more active and better able to function, tumors developed less fibrosis, and they responded more strongly to combination treatment.
Datta said the strategy focuses on changing the environment around the cancer cells so existing therapies can work better.
“Moving this work into a clinical trial is a landmark development for our GI cancer program at Sylvester,” Datta said. “We’re testing a clear, patient-centered strategy to disrupt IL1RAP using a treatment plan that can be delivered in the clinic.”
Because patients in the planned trial will receive treatment before surgery, researchers will be able to examine tumors before and after therapy.
“Every new approach helps us learn more,” said Peter Hosein, M.D., co-author of the study, co-leader of the Gastrointestinal Cancers Site Disease Group at Sylvester, associate director for clinical research at SPCRI and professor of clinical medicine at the Miller School. “This trial gives us a unique window to connect the science directly to patient outcomes, which is essential for moving the field forward.”
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