VA Researcher Works to Find Improved Therapies for Esophageal Cancer

By Stephen Spotswood

James Donahue, MD

BALTIMORE—James Donahue, MD, has been thinking about the need for better treatments for cancer his entire adult life. His mother died from breast cancer when he was 14, and from that day forward his course has been clear: Find a way to increase survival rates for cancer patients.

“Since that time, I’ve been motivated to pursue cancer research. I’ve taken different turns throughout my career, but that’s how I got to doing what I do,” Donahue explained. A thoracic surgeon and researcher at the VA Maryland Health Care System, Donahue splits his time between the operating room and the lab, where the focus of his research is discovering the mechanisms involved in esophageal cancer.

“There have been many studies on lung cancer, but not nearly as much on esophageal,” he said. “I found I can make a niche here; I have a better chance of making an impact.”

Overshadowed by the more pervasive lung cancers, esophageal cancer still results in more than 15,000 deaths every year, 75% of them in men. It’s the seventh most common cause of cancer death in men and has a five-year survival rate of 18%. At the VA, where the patient population skews older and male, esophageal cancer is seen at nearly four-times the rate of the general population.

“It’s a tough disease, and there have been no new therapies in years. While lung cancer is the leading killer, and esophageal cancer is not nearly as common, it’s becoming more and more lethal,” Donahue explained. “For a lot of cancers, there are screening programs set to detect them early. There’s not really a good screening program for esophageal cancer.”

The result is that, when people develop noticeable symptoms, such as trouble swallowing, the cancer is already relatively advanced. This makes finding better treatments even more urgent.

Donahue is looking for those better treatments by examining specific microRNA molecules that contribute to cancer growth and chemotherapy resistance. “We’ve identified a few specific microRNA that are really not expressed at all in cancer cells but are expressed in normal cells. As cells go from normal to cancer, they lose the expression of these microRNA. What we’ve found is that these microRNA try to regulate or keep at bay proteins that are important for cancer. These are proteins that protect cells from chemotherapy, cells that feed cancer.

“One of the first goals is to define as clearly as possible which individual microRNAs are important in human esophageal cancer,” Donahue explained. “We know it’s not going to be the same pattern in every single cancer. But, even if we could identify groups of cancers that show different expression patterns for the microRNAs, that would be a big step forward.”

The next step would be taking that knowledge and applying it toward a clinical treatment.

“Once we know what’s important in human cancers, we can examine how we can manipulate that,” Donahue recounted. “It’s an emerging technology, but there are ways now to actually use RNA-based medicine. The end goal is to treat tumors with microRNAs themselves; inject microRNAs that have been previously lost by those cells. We could also use a similar kind of medicine to silence or block microRNAs that [assist cancer].”

The other end-goal of Donahue’s research is to better identify and understand the proteins that these microRNA regulate. “A lot of these proteins have medicines or inhibitors that are already made for them. They’ve just not been used on esophageal cancer. For example, one of the proteins we’ve found is called survivin. There are small molecule inhibitors for that protein.”

One of the very few positive aspects of esophageal cancer presenting in such an advanced stage is that it’s an easier cancer to access. That means that, once these treatments have been developed, getting them directly into the tumor site will be much simpler, as will taking biopsies to determine the medication’s effect.

That step—actually injecting a microRNA-based treatment into an esophageal cancer patient—is still several years away. Having identified these microRNA in cell lines in the lab, Donahue and his colleagues now have to confirm that these are the molecules that are up- or down-regulated in human tumors.

His work has not gone unnoticed. It was announced last month that Donahue has been selected for a VA Merit Review Award—a four-year, $650,000 award that will help fund his research. “It will have an enormous impact,” Donahue declared. “Without that, we wouldn’t be able to continue.”

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