New biobank coordinates IBD biomarker research

Biomarkers have generated enormous scientific and clinical interest because of their diagnostic and prognostic potential. Although the field is still young, serologic and genetic markers are expected to play an increasingly significant role in a more individualized approach to health care where therapy is tailored to unique genetic or molecular profiles.

With this in mind, Mayo Clinic has instituted an inflammatory bowel disease (IBD) serum and tissue biobank involving all four Mayo campuses — Arizona, Florida, Minnesota and the Mayo Clinic Health System.

Jonathan A. Leighton, M.D., and Shabana F. Pasha, M.D., lead the Arizona biobank project. "We're trying to understand IBD better and one of the ways to do that is to collect specimens from patients who have ulcerative colitis (UC) and Crohn's and then combine research at all the sites to identify biomarkers of significance that can help with diagnosis, prognosis and even treatment down the road," Dr. Leighton says. "The four sites together see a large number of IBD patients, and we thought a four-site biobank would be very powerful."

In Arizona, Mayo researchers are collaborating with Arizona State University's Biodesign Institute, where Joshua LaBaer, M.D., Ph.D, one of the nation's foremost experts on protein biomarkers, directs the Virginia G. Piper Center for Personalized Diagnostics. Dr. LaBaer's laboratory recently discovered a panel of 28 autoantibody markers that may aid early diagnosis of breast cancer.

"His lab has a novel protein microarray technology— the nucleic acid programmable protein array, or NAPPA — that can test large numbers of proteins that may be significant biomarkers for IBD," Dr. Leighton explains.

Dr. Pasha adds, "Historically, antimicrobial antibodies have been surrogate markers for inflammatory bowel disease. But we are looking for autoantibody markers."

Antibodies against Saccharomyces cerevisiae (ASCA) and neutrophils (pANCA) have been used as diagnostic markers for IBD for years, but their usefulness is limited due to low specificity and sensitivity. "We use these serologies to some extent if a diagnosis isn't clear," Dr. Pasha says. "Most commonly, we would use them if a patient has some inflammation and other tests — capsule endoscopy and MR enterography — aren't able to differentiate between UC and Crohn's. These serologic tests are better for differentiating UC from Crohn's disease but are not so good for diagnosis because of the high false-positive rate."

Dr. Leighton points to another challenge. "Right now, I think that to talk about UC and Crohn's disease is an oversimplification. I firmly believe that IBD is probably a set of several different diseases that may look the same clinically but are different on the pathogenetic level. We only know the clinical expression, but we don't know what's going on beneath that, which may be why the sensitivity and specificity of the serologic tests we now have just aren't very good."

Moreover, current serologic tests are not definitively validated. Lack of validation is one of the critical challenges in biomarker discovery, driven primarily by overinflated expectations, which lead to underpowered validation studies, and concerns about return on investment. "Biomarkers cost so much to discover that they're not fully validated before they're taken to market," Dr. Pasha says. "We want to discover biomarkers, but we also want to clearly validate them to ensure they are useful and predictive."

Additional biomarker projects

Researchers at Mayo Clinic in Arizona are involved in two other biomarker programs not directly related to the biobank. In conjunction with Yale University and the University of Arizona, they are investigating TAM proteins and protein S, which appear to down-regulate the immune system and may play a role in the pathogenesis and treatment of IBD. These proteins may also serve as potential serum biomarkers of disease severity. Findings appeared in the July 2013 issue of Immunity.

Arizona researchers are also collaborating with Sandra J. Gendler, Ph.D., whose lab focuses on the role of MUC1 mucin in cancer, on a study of MUC1 expression in mouse models of colitis. Research was published in the Sept. 13, 2013, issue of Clinical Cancer Research.

"Right now," Dr. Leighton says, "there aren't many good, noninvasive ways of diagnosing and assessing disease activity. Biomarker discovery is exciting precisely because it has the potential for noninvasive diagnosis and management of patients."

Biomarkers may one day also emerge as tools for individualizing treatment. "We received funding from Mayo's Center for Individualized Medicine," Dr. Pasha says, "and that's the direction we want to explore."

Other biobank investigators

Leading the biobank program at Mayo Clinic in Florida are John R. Cangemi, M.D., and Michael F. Picco, M.D.

In Minnesota, biobank investigators include William A. Faubion, M.D., and Laura E. Raffals, M.D.

Michael D. Van Norstrand, M.D., Ph.D., heads the Mayo Clinic Health System biobank program.

For more information

Carrera Silva EA, et al. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response Immunity. 2013;30:160.

Poh TZ, et al. Downregulation of hematopoietic MUC1 during experimental colitis increases tumor-promoting myeloid-derived suppressor cells. Clinical Cancer Research. 2013;19:5039.