Worth a Pound of Cure

Physician-scientist Andrew Dannenberg, MD, collaborates with scientists around the globe in the quest to prevent cancer

By Beth Saulnier

Photographs by John Abbott

Andrew Dannenberg, MD, has spent the past two decades studying cancer. He has approached the disease from bench to bedside, explored its relationship to everything from smoking to viruses to painkillers, and collaborated with scientists around the world; he has published more than 150 articles, won awards, and served on the editorial boards of prominent journals. But in the end, all of that effort can be distilled down to one word: prevention.

"As a physician-scientist, my goal was always to work on issues that would be of value for the general population," says Dannenberg, the Henry R. Erle, MD–Roberts Family Professor of Medicine at Weill Cornell and director of the Weill Cornell Cancer Center. "I hope that any progress I make translates to clinical benefit—and it's my belief that more emphasis should be placed on efforts to prevent cancer. That doesn't mean that I'm not devoted to developing new and improved therapies. It's just that, from a societal standpoint, I think more emphasis should be placed on preventing disease."

Over the past few years, Dannenberg has been working to spread the word about the causal relationship between infection and cancer: he says that more than 20 percent of cancer cases worldwide can be traced to viruses, bacteria, or parasites. "It's quite a startling number. I don't think the public is sufficiently aware of the link between chronic infection and cancer." With the advent of the Gardasil vaccine to protect young women from four types of human papillomavirus (HPV), Americans have become more aware of the relationship between HPV and cervical cancer. But they may not know that the same virus is closely connected to throat and oral cancer (an argument for vaccinating boys as well), that chronic hepatitis B and C can lead to liver cancer, or that Helicobacter pylori can cause stomach cancer.

What do those underlying conditions have in common? Inflammation, the body's response to infection. Dannenberg has become one of the world's leading authorities on the link between chronic inflammation and cancer—a relationship that he says goes far beyond the one-fifth of cancer cases caused by infectious diseases. Long-standing inflammation of virtually any tissue increases the risk of cancer, and a clearer understanding of the mechanisms underlying the inflammation-cancer connection should provide the basis for strategies to reduce cancer risk.

Dannenberg's lab has focused its efforts on a network of genes that control the synthesis (COX-2, mPGES-1) and inactivation (15PGDH) of pro-inflammatory prostaglandins (PGs). Working with a multidisciplinary team of investigators including his longtime collaborator Kotha Subbaramaiah, PhD, the Jack Fishman Associate Professor of Cancer Prevention, Dannenberg's lab discovered that the COX-2 gene was over-expressed in a variety of premalignant and malignant conditions leading to increased levels of PGs—and that inhibiting the COX-2-PG pathway protected against the formation and growth of experimental tumors. PGs promote tumorigenesis by a number of mechanisms. For example, Dannenberg and colleagues described how the COX-2 enzyme's production of PGs increases formation of aromatase—which, as the producer of estrogen, plays a vital role in breast cancer.

Fat cells

In 2004, their work made national headlines after an article in the Journal of the American Medical Association reported that use of aspirin—an inhibitor of COX-derived PG synthesis—could dramatically lower the risk of developing hormone receptor-positive breast cancer, which makes up about 70 percent of cases in postmenopausal women. They began working in cell culture and confirmed their findings in a mouse model—concluding that over-expression of COX did indeed lead to an increase in aromatase. The researchers then wondered whether the findings could be extended to women.

"The question became, how the heck would I test this idea in real time?" Dannenberg recalls. "I struggled. I did not know what to do. And then I thought to myself, I have colleagues at Columbia who have just completed this well-known breast cancer study. I knew they had collected a wealth of data concerning use of aspirin, so I went to them with a molecular hypothesis. Based on our preclinical studies, we hypothesized that use of aspirin, an inhibitor of PG production, might suppress aromatase levels and thereby protect against hormone receptor-positive breast cancer." Dannenberg asked the epidemiologists to interrogate their database. The findings: women who reported having ever taken aspirin showed a 26 percent reduction in hormone receptor-positive cancer, but no meaningful drop in the receptor-negative version. "As a physicianscientist, I found it gratifying," Dannenberg recalls. "Here we were demonstrating, albeit in a retrospective study, that use of aspirin, an inhibitor of pro-inflammatory PG production, led to a statistically significant reduction in hormone receptor-positive breast cancer— but it had no effect on hormone receptor-negative breast cancer, consistent with our preclinical findings."

"This work has tremendous potential for public health impact," says Clifford Hudis, MD, chief of the Breast Cancer Medical Service at Memorial Sloan-Kettering Cancer Center, a professor of medicine at Weill Cornell, and one of Dannenberg's longtime collaborators. Still, Hudis and Dannenberg stress that they don't recommend that all women take aspirin specifically for breast cancer prevention. Despite the drug's potential benefits—also protecting against heart disease—it can have serious side effects, such as stomach ulcers and brain hemorrhage. "What I can say is that for those who are taking aspirin for other reasons, there is likely to be a benefit in reducing cancer risk," Dannenberg says. He and his collaborators continue to work on the link between pro-inflammatory PGs and aromatase with the goal of developing pharmacological or dietary strategies to reduce breast cancer risk.

Andrew Dannenberg, MD

In a related line of investigation, Dannenberg and his collaborators are working on inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), a condition that predisposes the patient to colorectal cancer. The mechanisms underlying the inflammation-cancer connection are being defined. "Many of the pathways that are aberrant in colitis are also altered in colorectal tumors," Dannenberg says. "In the short term, these mechanisms promote wound healing—but left unchecked, they lower the threshold for tumor formation." The ongoing work promises to provide new insights into the link between colonic inflammation and colorectal cancer that may result in risk reduction strategies. Another goal is to develop a personalized approach to reduce colonic inflammation.

Dannenberg says that more than 20 percent of cancer cases worldwide can be traced to viruses, bacteria, or parasites. ‘It’s quite a startling number,’ he says. ‘I don’t think the public is sufficiently aware of the link.’

Dannenberg's current work also includes exploring how one of America's most pressing health issues—the fact that a third of the population is overweight and another third is obese—may also portend a rise in cancer diagnoses. "One of the things that we're interested in pursuing now is obesity as a public health crisis," says Dannenberg. "Most people don't appreciate that obesity isn't just a risk factor for diabetes or heart disease, but also for cancer." Obese patients, he notes, are predisposed to a number of different cancers, including those of the breast, colon, endometrium, pancreas, and esophagus. "Obesity causes a sub-clinical inflammatory state," he says. "It's not like having a hot knee—if you have arthritis in your knee, you know about it. But in fact obesity can lead to inflammatory cells infiltrating tissues. So in addition to weight control there may be pharmacological or dietary strategies to suppress inflammation and thereby assist in reducing the personal risk of developing cancer."

Production of PGs, he notes, is sensitive to diet—so ingesting some types of fish and other foods that contain omega-3 fatty acids could reduce PG levels and suppress inflammation. By contrast, other types of dietary fat may be pro-inflammatory. "Working in close collaboration with Louise Howe, PhD, associate research professor of cell and developmental biology at Weill Cornell, and Dr. Subbaramaiah, we are actively investigating the effects of different dietary lipids on PG levels and related inflammatory mediators in preclinical models," says Dannenberg. "Of course, the long-term goal of this work is to be able to make evidence-based dietary recommendations. It is absolutely reasonable to believe that diets can be tailored to modify personal risk, but careful, mechanistic benchto-bedside studies are required. It's our view that, on a population basis, this type of work illustrates the potential of employing diet to reduce cancer risk."

Trained as a gastroenterologist, Dannenberg earned his MD from Washington University in St. Louis and did his residency and fellowship at Weill Cornell. Although he no longer sees patients, he is every inch the physician-scientist, colleagues say. "He is a remarkable person and has amazing energy," says Babette Weksler, MD, professor of medicine at Weill Cornell. "He organizes a complicated laboratory—people coming from all over the world, young scientists, young surgeons who often have had no background in the lab— and everyone goes away well trained and with a good paper under his or her belt. It's a lot of different people working together and all learning a great deal. Going to his lab meeting every week is one of my pleasures."

Both Hudis and Weksler laud Dannenberg for his skills as a collaborator, as well as for his ability to place his work into a broader context. "He is driven and passionate beyond belief—in a very good way," Hudis says. "He's also extremely and appropriately self-critical. When he's presenting an idea, he's the first person to point out if there's something potentially wrong with it, which is the way good scientists work. I find him inspiring to collaborate with, because he works so hard, in such a tightly focused way, and pursues a specific problem to the end. When you're with Andy, the system that his lab is focused on becomes the most important thing on Earth."