Blocking IL1RAP, a receptor involved in inflammatory signaling, can disrupt the tumor-driven inflammatory network that helps pancreatic cancer resist treatment, according to new research released on June 22 by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. The findings are advancing toward a neoadjuvant clinical trial that will combine IL1RAP-targeted therapy with chemoimmunotherapy in patients with operable pancreatic cancer before surgery.
Pancreatic cancer is considered one of the most difficult cancers to treat due to its tumor microenvironment—a complex network of cells that enables tumors to resist chemotherapy and immunotherapy. While recent advances have introduced KRAS-targeted therapies for metastatic cases, researchers say these developments may take years to benefit patients with operable disease and emphasize the ongoing need for new strategies.
In a study published in JCI Insight, Jashodeep Datta, M.D., and colleagues demonstrated how IL1RAP connects tumor cells, immune cells, and fibroblasts into a coordinated network sustaining 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, who is co-leader of the Gastrointestinal Site Disease Group at Sylvester and senior author of the study.
Preclinical research by the team found that inhibiting IL1RAP reshapes the tumor microenvironment: immune-suppressive cells decrease while T cells become more active; tumors show less fibrosis and improved response to combination therapy. Datta said the aim is not only to attack cancer cells but also "to reprogram the environment that protects them," thereby enhancing existing treatments.
Based on these results, Sylvester Comprehensive Cancer Center is advancing a neoadjuvant clinical trial combining IL1RAP-targeted therapy with chemoimmunotherapy prior to surgery for operable pancreatic cancers. "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."
Peter Hosein, M.D., co-author of the study and associate director for clinical research at SPCRI as well as professor at Miller School of Medicine, said, "Every new approach helps us learn more. This trial gives us a unique window to connect the science directly to patient outcomes, which is essential for moving the field forward." The work has received support from a Translational Research Grant from the V Foundation after national peer review.
