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Researchers have identified a promising way to weaken one of pancreatic cancer’s key defenses against treatment. The approach focuses on blocking IL1RAP, a receptor that plays a central role in inflammatory signaling and helps coordinate the network of cells surrounding pancreatic tumors.
The work, led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, is now moving toward a first-of-its-kind neoadjuvant clinical trial. The planned trial will combine IL1RAP targeted therapy with chemoimmunotherapy in patients with operable pancreatic cancer before surgery.
Why Pancreatic Cancer Is So Hard To Treat
Pancreatic cancer remains among the most challenging cancers to treat successfully. One major obstacle is the tumor microenvironment, the complex community of cells and structural tissue surrounding a tumor that can help cancer survive and resist therapy.
Recent attention has focused on a new KRAS targeted therapy that can extend survival in patients with metastatic cancer. However, bringing that treatment approach to patients with operable pancreatic cancer is expected to take years, leaving an urgent need for additional strategies for people whose tumors can still be surgically removed.
In the new study, published in JCI Insight, Jashodeep Datta, M.D., and his colleagues describe how IL1RAP helps link tumor cells, immune cells and fibroblasts into a coordinated system that supports resistance to treatment.
Pancreatic tumors do not survive on their own. Instead, they depend heavily on neighboring cells that help them adapt, grow and withstand therapy.
“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.
Disrupting Pancreatic Cancer’s Inflammatory Network
Because IL1RAP acts as a shared control point for multiple inflammatory signals, blocking it may interfere with a much broader tumor-supporting network.
That matters in pancreatic cancer because tumors often create an environment that is highly inflamed while also suppressing the immune system. This “inflamed but immune-suppressed” state is one reason chemotherapy and immunotherapy can be less effective. High levels of IL1RAP appear to help maintain both tumor growth and resistance to treatment.
If IL1RAP is helping sustain the tumor’s protective system, disrupting it could make those defenses easier to break down.
In preclinical studies, the Sylvester team found that inhibiting IL1RAP changed the tumor microenvironment in several important ways. Immune-suppressive cells became less abundant, while T cells became more active and better able to function. The tumors also developed less fibrosis and responded more strongly to combination treatment.
Rather than focusing only on killing cancer cells directly, the strategy is designed to alter the surrounding environment that protects them. Datta explained that this could allow existing therapies to work more effectively.
From Preclinical Research to a Clinical Trial
By identifying IL1RAP as a possible therapeutic vulnerability and connecting its activity with treatment response, the researchers have created a foundation for testing the strategy in patients.
Based on the early-stage findings, Sylvester is now advancing a neoadjuvant clinical trial that will combine IL1RAP targeted treatment with chemoimmunotherapy in patients with operable pancreatic cancers prior to surgery.
“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 will receive treatment before surgery, researchers will be able to examine tumors both before and after therapy. That provides an unusually direct opportunity to see how the biology of each patient’s cancer changes in response to treatment.
“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.”
Support for Moving the Research Into Patients
The research is supported by a highly competitive Translational Research Grant from the V Foundation awarded to Datta and his team. The project is part of a small group of translational research efforts selected each year.
Grant nominees undergo a rigorous national peer review process before being chosen. Selected teams receive $800,000 over four years to support “bench-to-bedside” research and help move promising new treatment strategies into early-phase clinical trials.