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DFCI’s balanced portfolio of scientific investments

The red and white flags suspended outside Dana-Farber Cancer Institute do more than simply decorate the hospital building; they sum up the dual mission inside: a dedication to discovery and commitment to care. “Our balanced portfolio, invested equally in research and patient care, makes us different from all other cancer centers,” says Chief Scientific Officer Barrett Rollins, MD, PhD. “No matter how you parse it -- by full-time effort, dollars spent, square footage -- the balance between the two is fifty-fifty.”

Commitment to a balanced portfolio, says Rollins, creates an environment in which clinicians and basic researchers find it easy to communicate and partner when opportunities arise to advance treatments in the clinic or illuminate discoveries in the lab. “Here’s one way this plays out,” he explains. “We have a single cafeteria where hardcore PhDs sit next to some of our biggest clinical rainmakers. I’ve watched projects bubble up as the result of these casual interactions across the clinical-research divide,” he says. “Collaboration is an essential part of this Institute.”

Collaborating for cures

One such collaboration began in 2000 and continues today between oncologist Patrick Wen, MD, clinical director of the Center for Neuro-Oncology at the Dana-Farber/Brigham and Women’s Cancer Center, and Charles Stiles, PhD, co-chair of DFCI’s Department of Cancer Biology and associate director of Basic Science at DF/HCC, whose research focuses on the genetics of brain development. The ultimate goal of their partnership? “To find small-molecule inhibitors that will cure patients with brain cancer,” says Stiles. “Targeted therapies look like the only game in town for a complicated organ like the brain.”

Joint interests led Stiles and Wen to their first clinical trial: a prospective analysis using Gleevec, which inhibits the PDGF receptor, known to be involved in glioblastoma. Stiles provided the preclinical evidence that convinced Novartis -- a company with which he’s had a long consulting relationship -- to fund a trial on glioblastoma patients. Wen, as principal investigator, sent tumor tissue of approximately 50 patients to Stiles, whose lab genotyped the tumors, looking for alterations in the PDGF receptor, as well as other mutations. Each subject received the drug in the hope that some might respond, but Gleevec by itself offered little benefit to these patients.

Today, among a host of other studies, Stiles and Wen are screening dozens of drugs -- including combinations of targeted therapies that hit multiple pathways, such as PI3K and EGFR -- to find the most promising candidates for clinical trials. Stiles’ lab evaluates the effectiveness of these drugs in tumor lines and intracranial tumor models; in upcoming trials, he will try to correlate the responders with genetic changes in the tumor. Eventually, the two scientists hope to conduct prospective clinical trials by genotyping patients and selecting those with the best chance of benefiting from a particular drug. “This collaboration has enabled us to find better drugs for trials,” says Wen. “Finally, after 20 years of no progress, some combinations of targeted therapies are starting to work.”

Diversification through innovation

While committed to a balanced portfolio that nurtures this type of collaboration, the Institute also has an abiding interest in diversifying within its research investments. Much as financial investors hedge their equity bets by diversifying across industries or countries, Dana-Farber has built a research portfolio across myriad areas of scientific promise. While the Institute actively supports traditional investigator-driven research into the fundamental processes that lead to cancer, its strategic plan also calls for results-driven integrative research centers that break down the barriers between disciplines and departments to accelerate innovative translational research in key fields.

“The eight centers are strategically identified areas we want to emphasize because they offer a high probability of improving outcomes,” explains Rollins. To receive its initial funding, each center had to prepare a detailed business and operating plan, including benchmarks and deliverables that would, according to Rollins, “achieve cost neutrality in three to five years.”

First to submit a plan was Marc Vidal, PhD, director of the Center for Cancer Systems Biology, which studies the effects of cancer-causing mutations within the context of the entire network of interacting proteins, or interactome. “Very rarely does a single mutated gene lead to cancer,” explains Vidal. “It’s important to understand the local perturbation of a gene mutation, but also to understand changes at the global scale of the interaction of all the molecules in a cell.”

The center creates models of the human interactome and uses them to answer questions about complex cellular systems and how disturbances lead to cancer. “It’s truly an integrative research center,” states Vidal, “which involves a half dozen labs and people with expertise ranging from computational science, biology, and clinical science to physics and engineering.”

In addition to its Flagship project, which is modeling the human interactome network, the center’s GoTo project shares technology, molecular libraries, computational resources, equipment, and information with scientists inside and outside DFCI. A third project, Think Tank, disseminates novel ideas through seminars and conferences focused exclusively on the questions of cancer systems biology.

To date, the CCSB has cloned about one-half of the library of protein-encoding open reading frames, generated a human interactome map containing nearly 3,000 novel protein-protein interactions, and developed about 60,000 short hairpin RNA reagents, in collaboration with the Broad Institute. It is now writing up results, which will be published in the next several months.

The concept of the integrative centers in general -- and the CCSB in particular -- evolved from a confluence of observations from strategic planners, Vidal, and many others that the enormous scale of cancer research requires a wider community effort across disciplines. “If you want to know what p53 binds to, you can solve that with two postdocs,” explains Vidal. “But if you want to know all 300 genes that are mutated in a tumor, you need 100 people with different know-how,” says Vidal.

This new way of doing research dovetails with a shift in the NIH funding process, which increasingly rewards collaborative projects. “In the aftermath of the Human Genome Project,” notes Vidal, “some questions have become so voluminous that the NIH is offering incentives for interdisciplinary centers.”

Reaching the underserved

“In cancer research, there are two ways to have a really big impact,” says Jane Weeks, MD, director of the Center for Population Sciences at DFCI and leader of the Outcomes Research Program at DF/HCC. “One is to put your head down in the lab and discover something completely novel that turns into a treatment, like Gleevec. Another is to have a small impact on a lot of people. That’s where population science fits in.”

The goal of the Center for Populations Sciences is to figure out why proven cancer therapies are not reaching everyone in the United States, to understand the barriers to care, and to change the system to overcome them. The center, which is building the framework to support research projects across a spectrum of disciplines and departments, focuses on three major areas: identifying cancer risk, reducing health disparities, and promoting public health -- especially among high-risk and underserved populations. “It’s amazing how many lives could be saved simply by getting good conventional cancer treatment out there to all who need it.”

Tucked under the umbrella of the center are two key initiatives: the Cancer Health Disparities Program, led by Karen Emmons, PhD, which conducts population-based research, designs and tests interventions, and initiates outreach activities to reduce cancer risk; and Cohort Studies of Patients with Cancer, led by Weeks, which tracks patients over time and has amassed a library of risk-factor, clinical, and outcome data as well as annotated specimens, which are available to laboratory, clinical, and translational investigators. The center also has created a new Data and Survey Core -- a tremendous boon to investigators -- staffed by experts who develop, test, deliver, and score surveys.

"What’s new in this center is that we now have people sitting with us whose primary appointments are in pediatric oncology, radiation, or surgery, so we’re truly interdepartmental,” says Weeks. “But our goal is to recruit some fulltime population-focused methodologists, like biostatisticians, who can help us address critical needs.”

Bridging the funding gap

Dana-Farber recently contrived a new mechanism for further diversifying its research portfolio, while bridging the growing gap in federal government funding. Among the approximately 40,000 grant applications received each year, the NIH supports only those with scores at or above the payline. Although this benchmark used to be the top 20 percent, it will likely shrink to 8 or 9 percent this year, according to Rollins. “If an investigator’s percentile score is too high to get funded but below the 16th percentile -- the NIH cutoff two years ago -- we will fund the project for a year,” he says, which will give the investigator time to reapply and achieve a better score. Why invest in these new projects? Rollins replies, “You never know which of these grant applications could result in the next big breakthrough.”