Pancreatic Cancer: Discovery Sparks New Clinical Trials

Pancreatic cancer is difficult to treat because it spreads quickly and has a distinct biochemical makeup. However, researchers achieved a significant advance by discovering the molecular alterations that occur during tumor migration—and they also discovered a medication that can hinder the process.

The next step is a groundbreaking clinical trial at the University of Rochester’s Wilmot Cancer Institute, which is scheduled to begin in early 2024 to test the drug discovered in the lab, according to senior investigator Darren Carpizo, MD, Ph.D., co-leader of Wilmot’s Genetics, Epigenetics, and Metabolism research program and chief of Surgical Oncology at the University of Rochester Medical Center.

“We will be the first institution in the U.S. to study the safety and effectiveness of the experimental drug, known as NP137, on pancreatic cancer that has spread to the liver,” Carpizo said.

The results of Carpizo’s bench science inquiry were published in the journal Cell Reports, and Carpizo will lead the Wilmot clinical trial alongside Aram Hezel, MD, chief of Hematology/Oncology at Wilmot, and Nabeel Badri, MBChB, a medical oncologist at Wilmot.

Pancreatic cancer has a five-year survival rate of only 12%, which is a minor rise from previous years in 2023. However, the number of cases is increasing globally, and pancreatic cancer is expected to be the second biggest cause of cancer deaths by 2030.

Why is pancreatic cancer so lethal?

For starters, it spreads (metastasizes) early in its growth. At the time of diagnosis, the disease had progressed outside of the pancreas in 85% of individuals. Even when the disease is limited to the pancreas and surgical excision is achievable, the majority of patients have cancer recurrence. Because metastasis leads these people to succumb to the disease, researchers are working to understand the biology of metastatic pancreatic cancer.

Second, although pancreatic cancer cells do not have to travel far to reach the liver, along the way they genetically reprogram themselves and become stronger. The result: newly seeded cancer cells in the liver have a distinctly different biology from the primary tumor in the pancreas, and are able to resist standard treatment, Carpizo said.

Wilmot researchers expanded on what was already known about Netrin-1, a critical gene associated in pancreas, breast, and colon cancers. For the first time, they revealed the intricate pathways that allow Netrin-1 to promote deadly genetic changes in pancreatic cancer cells as they migrate to the liver. They also demonstrated how Netrin-1 activates hepatic stellate cells, which are implicated in liver fibrosis, a dangerous chronic illness that predisposes the liver to cancer.

When researchers reduced Netrin-1 with the anti-cancer medication (NP137) in mice and tissue tests, cancer was less likely to spread and cancer cell death occurred. Scientists from Rutgers University, where Carpizo worked as a surgeon-scientist until joining Wilmot in 2020, and Fox Chase Cancer Center in Philadelphia are among those on the team.

For more information: Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling, Cell Reports.

DOI: 10.1016/j.celrep.2023.113369