Pancreatic tumors are surrounded by a protective
Pancreatic tumors are surrounded by a protective “nest” made of fibrotic scar tissue and the cells that manufacture it (red). A new study in mice demonstrates that disrupting this fibrous tissue makes immune therapy and chemotherapy more effective in attacking tumors of the pancreas. [DeNardo Lab]

Pancreatic cancer is a particularly troubling diagnosis, as most of the tumors are extremely aggressive and often unresponsive to traditional chemotherapy regimens. Moreover, in recent years immunotherapy has proven effective in treating various types of cancer, especially melanoma and carcinomas of the lung, yet so far, pancreatic tumors have remained impervious to immune-based therapies.

However now, investigators from Washington University School of Medicine in St. Louis (WUSM) have published new findings conducted in mice, which showed that immunotherapy against pancreatic cancer could be effective when given in conjunction with drugs that break up the fibrous tissue in these tumors. Based on these preclinical results, physicians are conducting a Phase I clinical trial in patients with advanced pancreatic cancer—testing the safety of the newly discovered drug combination when given alongside standard chemotherapy.

“Pancreatic tumors are notoriously unresponsive to both conventional chemotherapy and newer forms of immunotherapeutics,” explained senior study author David G. DeNardo, Ph.D., assistant professor of medicine at WUSM. “We suspect that the fibrous environment of the tumor that is typical of pancreatic cancer may be responsible for the poor response to immune therapies that have been effective in other types of cancer.”

The findings from this study were published recently in Nature Medicine through an article entitled “Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy.”

Unlike other cancer types, pancreatic tumors are characterized by large amounts of what the researchers describe as scar tissue. This extra connective tissue and the cells that deposit it, provide a protective environment for cancer cells, limiting the immune system’s ability to attack the tumor cells and restricting cancer's exposure to chemotherapy delivered through the bloodstream. The research team investigated whether some of this protection might be lost if they could disrupt the proteins that help fibrous tissue adhere to itself and surrounding cells.

“Proteins called focal adhesion kinases are known to be involved in the formation of fibrous tissue in many diseases, not just cancer,” Dr. DeNardo noted. “So we hypothesized that blocking this pathway might diminish fibrosis and immunosuppression in pancreatic cancer.”

Focal adhesion kinase (FAK) inhibitors have been developed for other areas of cancer research, but this was the first instance of testing them against pancreatic cancer in conjunction with immunotherapy. In the current study, an investigational FAK inhibitor was given in combination with a clinically approved immune therapy that activates the body's T cells and makes tumor cells more vulnerable to attack.

The scientists utilized a mouse model of pancreatic cancer and found that when given either a FAK inhibitor or immune therapy alone the mice survived no longer than two months. Adding FAK inhibitors to standard chemotherapy improved tumor response over chemotherapy alone. However, the three-drug combination—FAK inhibitors, immune therapy, and chemotherapy—showed the best outcomes, more than tripling survival times in some mice. Astonishingly some mice were still alive without evidence of progressing disease at six months and beyond.

The success of this mouse study provided a strong rationale for testing this drug combination in patients with advanced pancreatic cancer.

“This trial is one of about a dozen we are conducting specifically for pancreatic cancer at Washington University,” remarked co-author Andrea Wang-Gillam, M.D., Ph.D., associate professor of medicine at WUSM. “We hope to improve outcomes for these patients, especially since survival with metastatic pancreatic cancer is typically only six months to a year. The advantage of our three-pronged approach is that we are attacking the cancer in multiple ways, breaking up the fibers of the tumor microenvironment so that more immune cells and more of the chemotherapy drug can attack the tumor.”








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