Mayo Clinic cancer investigator builds prodigious research network

May 29, 2008

By hammersmith

By Matt Ellsworth, Flinn Foundation

Multiple myeloma is a relatively rare form of cancer, accounting for around 1 percent of all cancer diagnoses. But even at that frequency, it affects a huge number of people: This year, in the United States alone, 20,000 people will be diagnosed with the disease, which is the second most-common cancer of the blood. For myeloma patients and many others living with cancer, the work of Rafael Fonseca is vital.

Dr. Fonseca, deputy director of the Mayo Clinic Cancer Center, has been a professor of medicine at Mayo Clinic’s Arizona campus since 2004. He arrived that spring from Mayo’s flagship campus in Rochester, Minn. to launch the Multiple Myeloma Research Program. In less than five years, forming relationships with local institutions like the Translational Genomics Research Institute (TGen) and Arizona State University, as well as with premier national research coalitions, he has helped catapult Arizona to the forefront of multiple-myeloma research.

Multiple myeloma, which mainly affects individuals over age 50, is an incurable but treatable plasma-cell cancer, a hematological disease that can lead to a range of complications, including anemia, osteoporosis, and sharply increased vulnerability to infection as a patient’s normal system of immune responses falters.

Dr. Fonseca, who earned his medical degree at Mexico’s Universidad Anahuac, began investigating myeloma in the 1990s during his clinical fellowship at Mayo’s Rochester campus, where he was developing his expertise in hematology and oncology.

“When I started my fellowship I wanted to be 100 percent clinical,” Dr. Fonseca says. “The more I delved into research, the more I enjoyed it, and when I finished, I wanted to spend half my time on research. I slowly built up my own program, received some initial grants and eventually was able to transfer down here. My colleagues in Minnesota think that it was just the weather that drove me down here, but there were other factors.”

In Rochester, Dr. Fonseca had been part of a 60-year-old effort to provide treatment for myeloma patients and solve the many riddles their disease poses. In Arizona, he would essentially be running a startup venture–though he had considerable resources to help him get off the ground.

Upon arrival, Dr. Fonseca began laying the groundwork for the Multiple Myeloma Research Program, taking advantage of the state’s reputation for fostering collaborative endeavors. He worked to establish ties with other researchers and institutions, angling to form a network of investigators that could make far more progress against myeloma than any isolated scientist or research group. His first critical task was convincing two leading scientists with whom he had collaborated frequently in the past, Leif Bergsagel and Keith Stewart, to join him in Arizona.

“The model for science from the old days, where you’re just sitting in a corner, doing research until one day you shout out, ‘Eureka!’ is long gone,” Dr. Fonseca says. “Effective research projects now are multi-researcher, multi-institutional, multi-million dollar efforts.”

The operation that Dr. Fonseca has built with Dr. Bergsagel and Dr. Stewart has that degree of reach and complexity. All three scientists focus on the genetic underpinnings of myeloma, but from somewhat different perspectives: Dr. Bergsagel studies the mutations that trigger myeloma, while Dr. Stewart is working to develop therapies matched to patients’ genetic profiles. Among Dr. Fonseca’s own current research interests is investigating the origin and progression of MGUS (monoclonal gammopathy of undetermined significance), a relatively common condition that in some individuals leads to myeloma.

While the possible causes of and potential treatments for myeloma remain the focus of much investigation, the biology of the disease is relatively well understood. In a healthy individual, plasma cells are produced when the body detects the presence of antigens–foreign substances, such as viruses or bacteria–that may cause infection. Plasma cells then secrete antibodies–proteins uniquely matched to specific antigens–that allow the immune system to recognize and attack those antigens.

In an individual with myeloma, abnormal plasma cells replicate uncontrollably and secrete an excessive amount of antibodies that the immune system cannot use. The cancerous plasma cells travel through the blood stream and lodge in bone marrow, where they multiply and form lesions, intruding on healthy bone marrow cells. These lesions develop in bones throughout the body–thus the term “multiple” myeloma–preventing adequate production of healthy plasma cells and antibodies necessary for the body to fight other pathogens.

In their work on myeloma, Dr. Fonseca and his colleagues are united in what he describes as thematic alignment–in this case, concentrating on the role of genetics in the disease. Aiming for such depth in a research domain is the same approach he takes in his broader role directing the Arizona branch of Mayo’s Cancer Center.

“We’re in a very competitive field, and so we have to be opportunistic, focusing on the areas where we’re able to demonstrate excellence,” he explains. “We do best when we provide thematic alignment in our areas of excellence and don’t try to be everything to everyone.”

In recruiting Dr. Bergsagel and Dr. Stewart, Mayo Clinic’s reputation for excellence in myeloma research had gone without saying. Dr. Fonseca stressed to his colleagues both the potential gains from their partnering efforts and the unique benefits of setting up shop in Arizona.

“Getting the three of us together to work on projects was enticing,” he says. “I also needed to show them what was going on in Arizona. They were coming from larger institutions [Dr. Bergsagel from Cornell University’s medical school, Dr. Stewart from the University of Toronto], and this was a different kind of environment for them. There was not such a program in place here, but there was a great need and a great opportunity for collaboration with other institutions.”

Many examples of those collaborations are close at hand. Some exist on a person-to-person level–for instance, Dr. Fonseca shares a grant to investigate myeloma with computational biologist Seungchan Kim of Arizona State University and the Translational Genomics Research Institute (TGen). Others unite larger teams of researchers and institutions–to wit, Mayo and ASU have an official clinical partnership providing for joint education programs, a joint seed-fund grant program, collaborative research in bioinformatics and bioengineering, and shared office space.

One particularly important early development for Dr. Fonseca was his 2004 joint appointment to the TGen faculty to lead a project exploring genomics-based targeted treatment of myeloma. The arrangement was rooted in the research-collaboration agreement signed by Mayo and TGen in Sept. 2003 to broaden areas of joint investigation. (TGen’s drug-development operations are also sited on Mayo’s Scottsdale campus.)

Recently, the Mayo-TGen relationship has become even more intertwined. In February the two institutions unveiled a new strategic alliance, which Dr. Fonseca helped to engineer, that involves the appointment of some 30 TGen researchers to membership in the Mayo Clinic Cancer Center. The alliance means more collaboration between scientists and greater access to each other’s findings and resources.

“Offering TGen staff membership in the Cancer Center reflects the maturity of our relationship,” Dr. Fonseca says. “The key thing is to find areas that are mutually beneficial toward both parties. Ours has been a very fruitful relationship.”

Such an approach, oriented toward partnership rather than competition between institutions, may be difficult to hammer out in terms of financial and intellectual-property issues–especially when research might yield new drug candidates or other therapies with the potential to produce revenue upon reaching the marketplace. But such an approach is popular with both government and private research funders, which are demonstrating through their grantmaking how much they value the exponentially greater potential of combined scientific resources.

For instance, to win a prestigious, five-year Specialized Program of Research Excellence (SPORE) grant from the National Cancer Institute to study multiple myeloma, Mayo teamed with the Boston-based Dana Farber Cancer Institute, each institution adopting projects suited to its areas of expertise. Dr. Bergsagel and Dr. Fonseca are principal investigators of Mayo’s projects under the grant; their research collaborators include several top scientists from TGen.

As another example, TGen is working with the Broad Institute of Cambridge, Mass., on a $6-million project to sequence the myeloma genome; both institutions are immediately making new data publicly accessible and have pledged not to patent the genome, stipulations of the funder, the Multiple Myeloma Research Foundation (MMRF).

Following similar principles, Dr. Fonseca is directing the Multiple Myeloma Research Consortium (MMRC) Tissue Bank. The MMRC, assembled by the MMRF in 2002, initially comprised four institutions, including Mayo, that pledged to share data and other details from their research and to publish articles together. Today the consortium includes 13 institutions, all of which are contributing to a bank of tissues samples–plasma cells and bone marrow–donated by myeloma patients.

Under Dr. Fonseca’s supervision, the tissue samples–some 900 have been donated to date–are made anonymous to safeguard patient privacy, annotated and processed uniformly, and then made available to myeloma researchers. Having access to a myeloma tissue bank is especially important to researchers, since the disease’s relative rarity makes it difficult to gather independently enough patients or samples for effective studies to validate new therapies, learn which drugs work best in different patients, and identify new targets for myeloma.

That the MMRC tissue bank is housed on Mayo’s Arizona campus is one more indication of how rapidly the state has become a global hub for multiple-myeloma research. Such a rapid transformation indicates to Dr. Fonseca the promise for Arizona’s broader bioscience sector.

“It’s going to take more time–the true challenge is to be sustained for the long term,” he says. “And we need to show the ability to convert research to profitable entities. But Arizona is doing well: We have an urban center and we have great researchers. The elements are here.”

For more information:

Rafael Fonseca, M.D.: Mayo Clinic Researcher Profile

Intro to Myeloma,” Multiple Myeloma Research Foundation

Buying a Cure: What business know-how can do for disease,” New Yorker, 01/28/2008

Joining Forces to Combat Multiple Myeloma,” New York Times, 08/17/2004