The Future of Pancreatic Cancer Treatment

By Diane M. Simeone, MD, Lazar J. Greenfield Professor of Surgery and Molecular and Integrative Physiology, University of Michigan Medical School, and President of the American Pancreatic Association

Posted on | By Diane M. Simeone, MD

Pancreatic cancer is one of the most deadly diseases. It’s difficult to diagnose, so it’s often not found till it’s quite advanced. It also spreads quickly, and is notoriously resistant to many of the chemotherapy and radiation treatments we currently use. Only about 3 percent of people with pancreatic cancer live more than 5 years after diagnosis. Despite the relatively small number of people who are diagnosed, it’s still the fourth most common cancer killer.

Why is it so challenging to treat? We don’t completely understand the molecular basis of pancreatic cancer, but research within my laboratory at the University of Michigan Comprehensive Cancer Center is focused on trying to understand this terrible disease.

In 2007, my team was the first to identify a small group of cells, called cancer stem cells, in tumors from patients with pancreatic cancer. We believe these stem cells are the key to finding an effective treatment and possibly someday a cure for pancreatic cancer.

Cancer stem cells are the small number of cancer cells that replicate to drive tumor growth. Researchers at the University of Michigan and elsewhere believe current cancer treatments sometimes fail because they are not attacking the cancer stem cells. Research in our laboratory has shown that pancreatic cancer stem cells are especially resistant to chemotherapy and radiation. By identifying the cancer stem cells, we can then develop new drugs to target and kill these cells.

This is particularly crucial for pancreatic cancer, where we have not had a significant improvement in the long-term survival rates over the last 1 to 2 decades. I believe that if we can target cancer stem cells within pancreatic cancer, we may have an avenue to really make a breakthrough in therapy for this awful disease.

Our research shows that just a few cancer stem cells are responsible for the growth and spread of pancreatic cancer. Unless these stem cells are destroyed, the cancer will return.

Once we found the cells, we next had to figure out how to target them directly. A number of promising agents targeting these cells are currently being tested in our laboratory in human tumors taken directly from patients and grown in immunodeficient mice. We have been able to identify drugs that target pancreatic cancer stem cells. These drugs block developmental signaling pathways important in stem cell function. Clinical trials are currently open to target cancer stem cells in at University of Michigan using several of these agents. Click here for more information.

Cancer stem cells may be one reason our current therapies are not effective against pancreatic cancer. But that accounts for fewer than 2% of the cells in a tumor. Stem cells aside, pancreatic cancer is biologically aggressive, and even the bulk of the tumor cells don’t respond well to chemotherapy or radiation.

This may be explained by a gene we found that is overexpressed in 90% of pancreatic cancers. Expression of this gene, Ataxia Telangiectasia Group D Complementing gene or ATDC, is on average 20 times higher in pancreatic cancer cells than in cells from a normal pancreas.

We found that ATDC not only causes the cancer cells to grow faster and be more aggressive, but it also makes the cancer cells particularly resistant to chemotherapy and radiation. By targeting this gene, we may be able to make cancer cells more sensitive to the therapies we already have in hand.

In addition, we found that ATDC is most highly expressed at the point when pre-cancerous cells become cancerous cells. ATDC was also linked to increased levels of a signaling protein called beta-catenin, which is known to play a key role in cancer development.

ATDC has potential as a target for developing future therapies. It could also help us determine when a patient has pancreatic cancer and when it’s chronic pancreatitis, a diagnosis that’s often difficult to make without surgery. In some cases, this may allow patients to avoid an operation.

A new Specialized Program of Research Excellence grant (SPORE) from the National Cancer Institute will help University of Michigan researchers move these studies forward. The 5-year grant will focus on finding new therapies to target ATDC, as well as ways to block a protein that could make pancreas tumors more sensitive to current chemotherapy and radiation treatments.

What we want to do is take learning from the lab directly to the patient. We’re always thinking with the idea of how we can translate our research into action for better patient care.

I see patients deal with pancreatic cancer every day. It’s tough to see what they have to go through. But it’s hard to find a better motivator than that to try to end this.

For more general information about research and clinical trials, visit  www.mcancer.org/pancreatic.

Article written by Diane M. Simeone, MD
Lazar J. Greenfield Professor of Surgery and Molecular and Integrative Physiology, University of Michigan Medical School, and...