A Smoking Gun for Pancreatic Cancer Process

Mouad Edderkaoui, PhD

A multi-center study led by Cedars-Sinai scientists has shown how cigarette smoking may cause pancreatic cancer. It also has uncovered a potential way to treat this disease, using a drug that is already approved by the U.S. Food and Drug Administration (FDA) for a different type of cancer. The study was published earlier this year in the journal Oncotarget.

Pancreatic cancer is one of the most lethal forms of the disease and the fourth leading cause of cancer-related deaths in the U.S. On average, only about 7 percent of patients are alive five years after diagnosis with this cancer, according to the American Cancer Society.

Although smoking has long been known to raise the risk of getting pancreatic cancer, the reason for this risk is not well understood, according to Mouad Edderkaoui, PhD, assistant professor of Medicine and Biomedical Sciences at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. Edderkaoui and his colleagues set out to solve this mystery.

Searching for clues, the scientists developed mouse models that showed precursors of pancreatic adenocarcinoma, the most common type of pancreatic cancer. When they exposed these laboratory mice to cigarette smoke, cancerous cells grew and multiplied. "Cigarette smoking induced a significant three-fold increase in pancreatic lesions," Edderkaoui said.

Exploring the process in the lab dish, the team found that cigarette smoke specifically activated the protein histone deacetylase-3 (HDAC3), which led the cancer cells to produce IL-6, another protein. IL-6 interacts with cells in the immune system, which normally fight cancer. But under the influence of IL-6, these immune cells changed their function and actually promoted the growth of pancreatic cancer in the mice and made the cancer cells susceptible to spread to other organs.

Stephen Pandol, MD

To confirm that this cancer-causing process might also apply to people, the researchers compared samples of normal-appearing and cancerous tissues taken from patients with pancreatic cancer. Among other evidence, they found that the cancerous tissues contained higher levels of IL6 than the normal tissues.

Taken together, the findings indicate that the seeds of aggressive pancreatic cancer — the type that breaks away from the pancreas and causes lethal metastasis — are planted in the early stages of the disease," Edderkaoui said.

The good news is that a drug exists that can counter, or inhibit, the action of the key player in this destructive process, the HDAC3 protein. The drug, suberoylanilide hydroxamic acid (Saha), was approved by the FDA in 2006 to treat another cancer, a form of T cell lymphoma.

When the Cedars-Sinai researchers administered Saha to their laboratory mice, it reversed the effect of smoking, allowed the immune cells to keep their original anti-cancer function and stopped the development of pancreatic cancer.

The investigators did not administer Saha to human subjects, and therefore their study did not show that Saha would have the same effect on patients with pancreatic cancer as it did on the mice. But their findings opened up that possibility. "Our study demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease," Edderkaoui said.

Edderkaoui was the first author for the Oncotarget article on the study. Stephen Pandol, MD, director of basic and translational pancreas research at Cedars-Sinai and professor of Medicine, was the senior author.