Effects of Proglumide with Chemotherapy on the Pancreatic Tumor Microenvironment: Phase 1 PROGEM Trial

Posted in Announcements

Jill Smith, MD, Ben Weinberg, MD, et al.

The PROGEM trial looked at a new way to treat metastatic pancreatic cancer: It combined standard chemotherapy with an older drug called proglumide.

Due to the fortress of dense, scar-like tissue called the desmoplastic stroma surrounding pancreatic cancer, it is notoriously difficult to treat because medicines cannot find a way in to attack it. 

This study suggests that proglumide might be the key to tearing down the fortress walls.

Proglumide

Originally developed decades ago for the treatment of stomach ulcers, proglumide is a drug that blocks cholecystokinin (CCK) receptors. In pancreatic cancer, activation of these receptors helps it grow and form the dense tissue fortress that protects it from cancer-fighting therapies.

The Phase 1 trial focused on safety and how proglumide affects the Tumor Microenvironment (TME)—the area immediately surrounding the tumor.

Safety

The combination of proglumide with standard chemotherapy (gemcitabine and nab-paclitaxel) was well-tolerated. There were no unexpected side effects, meaning it didn’t make the already-tough chemotherapy harder for patients to handle.

Breaking Down the Fortress

By looking at tumor biopsies, researchers saw that proglumide actually “remodeled” the tumor’s surroundings:

  • There was a significant reduction in collagen, the fibrous tissue that makes pancreatic tumors so hard and dense.
  • There was a decrease in M2 macrophages, immune cells that usually help tumors hide and grow.
  • There was a significant increase in CD8+ T cells and Natural Killer cells—the body’s “warrior” cells that can actually kill cancer.

Pain Relief

Pancreatic cancer is often very painful. Patients in the study reported less pain by the end of treatment or at 24 weeks after starting it if they were still undergoing therapy when assessed. This suggests that proglumide might help improve patient quality of life while it battles the disease.

Why This Matters

Pancreatic tumors are often called “cold” tumors because the immune system can’t get inside them and can’t react to them. This study shows that proglumide helps turn them “hot” by:

  1. Thinning the scar tissue so chemotherapy can get in.
  2. Activating the immune system to help fight the cancer.

What’s next? 

Because this was a Phase 1 trial (small and focused on safety), the next step will be larger trials to determine how much longer patients live when proglumide is added to their treatment plan.