Established in 1970 as a small clinic for cancer patients, the Georgetown Lombardi Comprehensive Cancer Center was named for football coach Vince Lombardi, who was treated for cancer at Georgetown University Hospital. In 1974 Georgetown Lombardi became the nation’s 16th National Cancer Institute (NCI)-designated comprehensive cancer center, and today remains the only such designated center in the Washington, DC, area. It has since evolved into a state-of-the-art center housing more than 240,000 square feet of clinic and Innovative Steps Toward Individualized Treatment research space, and is part of both Georgetown University Medical Center and Georgetown University Hospital.
Today, 500-plus staff members, including 175 clinicians and researchers, work together to “improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future.” Evidence of the commitment to this mission can be found in every aspect of patient care and research at Georgetown Lombardi, but it is especially apparent in 2 new innovative programs that promise to significantly advance both research and patient care: the Ruesch Center for the Cure of Gastrointestinal (GI) Cancers and the Georgetown Database of Cancer (G-DOC).
John L. Marshall, MD
Now in its second year of operation, the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers has its roots in the philanthropic gift of Jeanne W. Ruesch, whose husband Otto died of pancreatic cancer. “Mrs Ruesch was determined that her gift be used to make a meaningful difference for those with GI cancers, and challenged us to bring to fruition what we envisioned as the ideal research-driven GI cancer center,” said John L. Marshall, MD, director of the Ruesch Center.
That challenge was especially intriguing to Marshall, who was painfully familiar with some very real shortcomings. “Awareness about GI cancers has been sorely lacking,” he said, “and our tendency to treat everyone’s GI cancers as if they were the same disease amounts to ignoring the ‘molecular elephant in the room.’” As Marshall and his team set about the task of making the ideal GI cancer center a reality, they did so based on a 2-pronged approach: to raise awareness among patients and advocates and to improve overall translational research for this group of cancers that, collectively, remains the number 1 cancer killer.
A significant piece of the initial funding was used to develop the Ruesch Center’s nurse navigator program, in which specially trained oncology nurses guide each patient through the treatment experience, ensuring that they see the right people at the right times. To date, efforts to increase awareness have included hosting periodic scientific symposia that bring to the forefront issues being grappled with by the research community, as well as patient– and caregiveroriented symposia that feature educational lectures on GI cancer research, nutrition, and wellness given by physicians and specialists. The Ruesch Center is also an active champion for GI cancer causes in the community, partnering with other advocacy groups in support of Washington, DC-area events to help drum up funding and support for GI cancer research.
“To say that there’s room for improvement in the area of treatment innovation for GI cancers is an understatement,” said Anton Wellstein, MD, PhD, Georgetown Lombardi’s associate director for basic science. Wellstein described survival rates for patients with pancreatic cancer as dismal, and noted that outcomes for patients with colorectal cancer have improved very little over the past 20 years.
“The opening of the Ruesch Center has given us the opportunity to bring together research and clinical practice, to use all our muscle to improve outcomes, and to determine which patients will most likely benefit from existing treatments and those in the pipeline,” he said. “Individualized therapy is the bottom line.”
Since its inception in 2009, drug development efforts at the Ruesch Center have been in step with the new era of targeted cancer treatments. “We now know the vulnerabilities of specific cancers based on mutations, and specific molecules have been developed to target those vulnerabilities,” said Wellstein. He noted, however, that it has been difficult to tailor trials to determine if this information would translate into actual patient benefit.
To address this difficulty, Georgetown Lombardi and the Ruesch Center, in close collaboration with the German cancer biobanking company Indivumed GmbH, have established a tissue repository that gives the Ruesch Center’s scientists a unique opportunity to determine the potential effects of both new and conventional therapies. In what Wellstein described as both an intense and tedious process, a broad range of samples (eg, blood, urine, surgical specimens) are painstakingly collected and prepared, giving researchers what they need to tease out which agents will have a drug effect and, ultimately, which of those drug effects will translate into a true therapeutic benefit. At present, the bank holds samples from more than 500 cancer patients.
“As a relatively small center, it won’t be feasible for us to conduct larger phase II and III trials on our own,” said Marshall. “But thanks to the tissue bank, we’re uniquely positioned to carry out highly enriched, early-phase trials with multiple data points for the most feared of the GI cancers, developing biomarkers as we learn why and how particular agents work. This is our role.”
In its first year of operation, the Ruesch Center touched the lives of more than 1500 new GI cancer patients and it is currently conducting 25 GI cancer trials. Since the initial endowment, the Ruesch Center has attracted additional philanthropic funding, which, in combination with funding obtained for individual scientists’ research, is allowing the Ruesch Center and its work to expand.
“The change in our ability to analyze molecular pathways has initiated an entirely new era of drug development, but someone has to make the push from the bench to clinical use,” said Wellstein.
When it comes to funding, however, innovation can be a double-edged sword. Marshall noted that many potential funders are looking for a regulatory endpoint. For this reason, bridge funding has been needed to support much of the Ruesch Center’s innovative efforts, and a fall symposium hosted by the Ruesch Center will look at value (versus safety and efficacy) as one such regulatory endpoint.
Both Marshall and Wellstein stressed that this type of funding takes creativity, the design of the trials can be exceedingly complex, and the collection and preparation of the samples for the specimen bank is anything but glamorous.
“There’s a huge difference between having a mission and actually following through,” said Wellstein. “Lombardi and the Ruesch Center have created an environment that is conducive to keeping our noses to the grindstone as we go about the day-to-day work that brings us closer to effective individualized therapy.”
Not surprisingly, this commitment to the behind- the-scenes work toward individualized care is at the core of another of Georgetown Lombardi’s innovative endeavors: namely, the G-DOC.
“The opening of the Ruesch Center has given us the opportunity to bring together research and clinical practice, to use all our muscle to improve outcomes, and to determine which patients will most likely benefit from existing treatments and those in the pipeline. Individualized therapy is the bottom line.”
–Anton Wellstein, MD, PhD
When Louis M. Weiner, MD, was named director of the Georgetown Lombardi Comprehensive Cancer Center in 2007, his vision for the Ruesch Center included “a novel approach to bringing advances in research and treatment into clinical practice.” That vision ultimately manifested as G-DOC.
G-DOC, which is still under development, is a series of databases containing detailed analyses of the cancers of several thousand patients, including molecular characteristics (ie, DNA, proteins, and other markers), findings from imaging scans, and treatment information. It is, in fact, estimated that every patient in the database will generate approximately 10^39 bytes of data for analysis.
The idea is to use G-DOC as a tool for comparing a particular patient’s clinical information to corresponding G-DOC data from every other patient with a similar disease. This, Weiner explained, will enable Georgetown Lombardi researchers to identify the clinical and molecular characteristics of a patient’s cancer that most reliably track with clinical outcomes (see “G-DOC at Work”). And this, in turn, will be a major step toward the personalized medicine so desperately needed to improve treatment outcomes.
“Without such a tool we’re essentially approaching newly diagnosed patients as we did back in the 1950s: taking a history, performing an exam, ordering lab and radiology studies, and using those results along with our experience and knowledge of the literature to formulate a treatment plan,” said Weiner.
While the cataloging of the Human Genome Project promised to produce vast quantities of information with unprecedented potential, Weiner noted that there was no way of incorporating that information into anything actionable. “As oncologists, we’ve been working at a disadvantage,” he said, “with no effective way to catalog, access, and generate the information needed to formulate truly individualized treatment plans. What G-DOC offers is the opportunity to analyze all genetic and other variations in the molecular profiles of patients’ cancers, and to use that information to come up with truly customized treatment plans.”
Louis M. Weiner, MD
Subha Madhavan, MS, PhD, whom Weiner recruited from the NCI to serve as Georgetown Lombardi’s first director of clinical research informatics, is charged with overseeing creation of the G-DOC infrastructure. According to Madhavan’s estimations, only 20% of available information about a patient’s cancer is actually used during the course of his or her treatment. She views G-DOC as a unique opportunity to make accessible to physicians the amount and types of information they need to tailor treatment more specifically and accurately to a patient’s particular disease.
Madhavan cited integration of validated “omics” results into electronic health records as the most potentially valuable contribution of G-DOC to mainstream clinical care. “This will enable the incorporation of real-time information, such as validated biomarkers and integrated clinical research findings, into the clinical care process,” she explained, adding that G-DOC makes information available in an easy-to-understand, highly summarized fashion that allows for rapid decision-making in a clinical setting—something other research databases do not do.
G-DOC is in step with a move toward the development of a collaborative information network that shares research data across multiple investigators and institutions—a well-described NCI initiative in the form of the Cancer Biomedical Informatics Grid (caBIG). G-DOC will employ the standards and best practices from caBIG and other large-scale informatics projects to help integrate patient data into its databases. Doing so also will enable researchers to identify key genes and proteins that may be responsible for various cancers, help to predict treatment response, and indicate the presence of increased risk for developing cancer.
Weiner noted, however, that the approach being adopted by Georgetown Lombardi is a bit different from that of the nationwide initiative in that it focuses on the patient rather than the disease. An ongoing colon cancer trial serves as an example. “We know that surgery is curative in 80% of patients with stage II colorectal cancer, while the remaining 20% of patients relapse and ultimately succumb to their disease,” he said. “G-DOC gives us the potential to identify and comprehensively analyze the molecular factors that track with relapse or cure, and to apply resources accordingly.”
Today, with more than 5 years of follow-up in an admittedly small study, Georgetown Lombardi scientists have identified molecular features in the colon that will enable them to predict whether or not surgery will be curative. The next step will be to develop a diagnostic panel to apply to the dataset. This, said Weiner, might take the form of a simple additional test performed at the time of diagnosis to more precisely determine surgical outcomes for individual patients.
Acknowledging that performing such detailed testing on every patient would never be financially feasible, Weiner noted that it is possible to test sufficient numbers to provide researchers with an understanding of how the findings relate to clinical outcomes. “The goal is individualized care,” he said. “Rather than simply telling a patient that her cancer is, for example, associated with a 50% cure rate, we’d be able to tell her that her particular disease doesn’t do well with conventional therapy ‘A’ and is most likely to respond to newer therapy ‘B.’” To this end, G-DOC scientists are working on incorporating multiple datasets from the broader cancer community, providing access not only to Georgetown Lombardi researchers, but also to scientists from other centers.
Subha Madhavan, MS, PhD
“Using the Georgetown Database of Cancer (G-DOC), we can, for example, test the hypothesis that there are reproducible gene expression differences that can be identified between recurring and nonrecurring estrogen receptor–positive tumors in tamoxifen-treated patients with node-negative breast cancer,” said Subha Madhavan, MS, PhD, Georgetown Lombardi’s director of clinical research informatics. “The G-DOC Web tool permits us to perform this analysis quickly and easily, using nothing but the rich, publicly available datasets obtained from the biomedical literature.” To support these data, published breast cancer study datasets (clinical and microarray experiment data) are uniformly processed using validated bioinformatics pipelines and are then loaded into G-DOC to be used as follows:
The potential benefits notwithstanding, an undertaking such as G-DOC is not without its challenges, including the limited resources and significant learning curve associated with any project of this scope. According to Madhavan, the most significant of those challenges thus far have been those related to data sharing. She said, “Clinicians and researchers still hold their data close to their hearts, and need to be incentivized (with tools, grants, etc) to make their data available through G-DOC.” The other major challenge identified by Madhavan lies in convincing physician scientists of the benefits of G-DOC. “While there are plenty of forward-looking clinicians who actually ‘get it,’ many physician scientists want to continue to manage their data in Excel spreadsheets,” she said.
Another major challenge posed by the data integration inherent in G-DOC is the wide variety of data sources that need to be combined into the single unified database. As a result, Madhavan and her team must laboriously match fields in 1 database to those in another, all the while ensuring the consistency of hundreds of factors, such as units of measurement and timing. Assisting with these efforts is Indivumed, which will provide a wide range of biospecimen data to add to the clinical databases at Georgetown Lombardi.
As with any endeavor that involves information sharing, Georgetown Lombardi scientists are extremely mindful of the ethical and legal requirements for confidentiality inherent in a project such as G-DOC. All studies are, of course, conducted with IRB approval, and can move forward in real time without accessing personal patient information.
“There’s no denying the complexity of this endeavor,” said Weiner, “but G-DOC represents the commitment of Georgetown Lombardi scientists and clinicians to address that complexity rather than run from it.”
Laura Bruck is a Cleveland, Ohio-based freelance writer and editor who has specialized in healthcare reporting since 1987.