A New Target Against Pancreatic Cancer

Pancreatic cancer is a horrible condition on many levels. In its early stages, it has few distinct symptoms and is easily confused with gastrointestinal or liver disorders. Also, pancreatic tumors recruit immune and other cells to generate a protective shell, or microenvironment, that helps them resist treatment. According to the National Institutes of Health, only about 8.5 percent of patients survive for five years.

Nagaraj Nagathihalli, Ph.D.

“It’s a bad disease and the third leading cause of cancer deaths,” said Nagaraj Nagathihalli, Ph.D., research assistant professor of surgery at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine. “Because of the difficulty diagnosing and treating this cancer, it’s a challenge to develop a good drug.”

As with lung and other cancers, smoking has a dramatic impact on pancreatic cancer, increasing the risk of developing the disease and reducing the ability to survive it. Between 20 and 30 percent of pancreatic cancer patients are current or former smokers. But in a paper published in the journal Cancer Research, Dr. Nagathihalli, who is corresponding author, and colleagues have shown that a protein, called CREB, could be a new and potent target.

While it has long been known that smoking contributes to risk of developing pancreatic cancer, no one had deciphered the precise mechanisms. In the study, the team showed that nicotine byproducts, called nitrosamines, activate CREB, which is only lightly expressed in normal pancreatic cells. Turning on CREB increased the risk of developing pancreatic tumors in animal models and inhibiting CREB improved survival.

This makes a lot of sense. CREB is part of pathway named after the protein Kras, which is mutated in 90 percent of pancreatic tumors. Unfortunately, drugs designed to target Kras have produced unimpressive results. A transcription factor, CREB is activated downstream of Kras and turns on a variety of genes. The nitrosamine/CREB connection provides a link between smoking and pancreatic cancer, as well as a potential therapeutic target.

But that’s only part of the story. Pancreatic cancers recruit immune cells into their microenvironment. These tumor-associated macrophages (TAMs) actually help pancreatic cancer survive and grow. Tumors also bring in regulatory T cells (Tregs), which turn off the cytotoxic T cells that should be attacking cancer.

“TAMs and Tregs help in the tumor microenvironment, and they help with the progression of the tumor,” Dr. Nagathihalli said. “But when we inhibited CREB, both populations were way down. That was one of the surprises in the study.”

The group wants to convert these findings into clinical trials to test whether inhibiting CREB in pancreatic cancer patients with a history of smoking will improve survival. This is all part of an overarching effort, orchestrated by the Pancreatic Cancer Action Network, to double survival by 2020.

Now that they have identified CREB as a potential therapeutic target for pancreatic cancer, Dr. Nagathihalli and others are looking at whether inhibiting the protein might be useful in other cancers.

“CREB is a key molecule in smoking-induced pancreatic cancer, but that may be true also in lung, colon, and oral cancers,” Dr. Nagathihalli said. “We don’t know yet and are investigating that with other labs.”

Sylvester co-authors were Supriya Srinivasan, Ph.D.; Tulasigeri Totiger, Ph.D.; Austin R. Dosch, M.D.; Fanuel Messaggio, Ph.D.; Yuguang Ban, Ph.D.; Nipun B. Merchant, M.D.; and Michael N. VanSaun, Ph.D.