Mary Catherine Calisto Systems Biology Initiative Workshop, October 11

• Systems Biology in the Clinic, WK Al Yung, MD
• Computational Research, Ernest Fraenkel, PhD
• Better Delivery Systems, Robert Langer, ScD and Giulio Draetta, MD
• Increasingly Valuable Work, Louis Beardell, Jr, JD
• Grant Presentations

The goal of our Mary Catherine Calisto Systems Biology Initiative is the use of systems biology research to discover and develop durable therapeutic strategies to eradicate or manage brain tumors, National Brain Tumor Society Chief Scientific Officer David Hurwitz, PhD, explained in opening remarks at the October 11 workshop.

“At its most basic level, we can talk about systems biology as the study of complex biological problems, as integrated and interacting networks of their components,” he said. “And we want to make sure that everything we’re supporting has a path to the therapeutic strategy, and, in fact, an actual strategy to go into the translational level."

As we are nearing the end of the first phase of the initiative, during which time researchers are conducting feasibility studies, our eyes are on the next phase, which will have a higher level of support yet strong expectations. Systems biology discoveries that can be translated into predictive tumor responses of therapeutic benefit, Dr. Hurwitz said, are paramount among those expectations. “So not only do you need to find something through systems biology but understand why what’s happening in your system is working.”

Systems Biology in the Clinic

“Systems biology is going to be the underpinning for us to make any progress in the therapeutic world,” proclaimed WK Al Yung, MD, chair and professor of neurology and neuro-oncology at the University of Texas M.D. Anderson Cancer Center. A renowned clinician and our strategic advisor, Dr. Yung discussed the clinical significance that systems biology will have. Right now in the clinic, the basic treatment for glioblastoma multiforme (GBM) is radiation therapy plus temozolomide chemotherapy, a paradigm that hasn’t changed in 10 years, Dr. Yung said. “But we’re still losing 90% of our patients.”

GBM is not one drug target; it is multiple targets. The Cancer Genome Atlas has classified GBM into four different types based on molecular profiles, and other groups are likely to classify the tumors into even more groups.

Right now, “the job for us to do is find out how many targets are important. Then we can develop the right drug and mix the drug in the right way so that we will be able to give the right package or right cocktail to the right patient,” Dr. Yung explained. He issued a challenge to anyone working in systems biology: “Help us to reduce all this genomic data into some form that we can use in the clinic.”

He then outlined a process by which systems biology could yield results. When a patient is diagnosed with a tumor, a clinician can do a biopsy and send that to the lab for analysis and identification of possible markers to target. The patient is treated with a drug or combination of drugs targeting that marker. The tumor is then surgically resected and analyzed to determine if the drug(s) affected the marker as expected, and why it worked or didn’t work, and if it didn’t, other combinations could be tested.

“We need systems biology’s help so we can tell from the get-go how we are going to segregate the patients [into treatment groups and determine] what basis we use to choose the drug,” Dr. Yung explained.

Computational Research

“So how do you take these quarter of a million protein-protein interactions and figure out which ones are reliable and which ones aren’t?” asked Ernest Fraenkel, PhD, associate professor of biological engineering at Massachusetts Institute of Technology. Dr. Fraenkel expanded on the complexity of GBM and described computational approaches within systems biology that can help to unravel the landscape.

“We need to know not just glioblastoma, but very precisely what kind of glioblastoma each patient has,” he said. “We have to get at the molecular basis of the complexity of every disease, and we really have new tools to understand what the right pathways are that we should be targeting.”

Systems biology provides a way to understand properties of systems of known components as well as a way to allow the data to tell us how to treat the relevant pieces of an unknown system. He described the ’omics technologies being used now and how it will take an integrated approach to understand the data being harvested.

“When you apply both proteomics and genomics in the same system, you get very different answers, because they’re answering different questions about what’s important in the system,” Dr. Fraenkel said. An integrated approach is necessary to find out where the technologies overlap, and his laboratory has taken a protein network modeling approach to that quest.

“’Omics technologies have the potential to tell us a lot of the unknowns in the biology of any system, and especially in something as complicated as glioblastoma,” he explained.

Other speakers that morning rounded out the discussion topics, including barriers to adequate drug delivery to the brain, getting funding for developing new technologies to deliver drugs, instituting new validation and evaluation processes early in the continuum of clinical trials, and adequately protecting the intellectual property of new technologies.

One significant barrier to brain tumor treatments is lack of bioavailability of drugs after they are administered. Because of the protection afforded by the blood-brain barrier, “generally what happens is that you’re lucky if you get 0.1 percent, actually one one-thousandth, into the brain,” said Robert Langer, ScD, professor of chemical engineering at the David H. Koch Institute for Integrated Cancer Research at MIT.

We Need Better Delivery Systems and More Validation

Better delivery systems are needed, and that is what Dr. Langer and others have been working on for many years, but it has always been an uphill battle to get funding for developing new technologies. “So I should just say one of the things, and it’s one of the reasons why your society is a good thing, one of the things that we faced when we started this, … was whenever you come up with a new idea, …, reviewers don’t like it,” leaving researchers to turn to funders such as NBTS in early stages.

Dr. Langer, who holds about 800 biopharmaceutical patents, invented the matrix material used in the Gliadel wafer brain tumor treatment. The early patents helped his lab to get funding needed to research drug delivery methods and materials.

“There has been, over the years, a lot of stuff that has gone into patients that did not have legs to stand on,” said Giulio Draetta, MD, director, Institute for Applied Cancer Science, and professor, University of Texas MD Anderson Cancer Center, including “poor quality agents, agents with little validation in terms of exposure, biodistribution, and delivery.” New trials should be designed around taking multiple biopsies at different stages of treatment.

“We want to make sure that, if we put a patient in a trial, we are in a position to get an early response, so that we don’t subject those individuals to unnecessary treatment for much longer, and possibly switch them to an alternative treatment if there is time,” Dr. Draetta explained.

Increasingly Valuable Work

Louis Beardell, JD, a counselor with the international law firm Morgan Lewis, expanded on the patent and intellectual property issues faced by today’s biomedical and systems biology researchers, as Dr. Langer mentioned earlier. “The biopharmaceutical industry is unique, cancer treatment is unique, and there is so much uncertainty that comes to getting funding and allowing investors a reasonable return on investment,” Mr. Beardell said.

Ability to identify new therapies will increasingly become valuable as we move toward a model of more personalized medicine. “Identifying which therapies will be appropriate for individuals, I think, there will be a significant amount of knowhow and proprietary technology that will go into that,” he explained.

Grant Presentations

In the afternoon session of the workshop, our grant-funded researchers discussed their initial efforts in systems biology research:

— Christopher Willey, MD, representing Markus Bredel, MD, PhD, of the University of Alabama at Birmingham discussed their integrated approach to the genomics and pharmacokinomics of GBM therapy.

— James Gallo, PhD, of Mount Sinai School of Medicine, talked about his work to overcome brain tumor resistance to molecularly targeted, anti-cancer drugs.

— Santosh Kesari, MD, of the University of California, San Diego, discussed his work in developing in silico systems biology directed toward personalize GBM therapy.

— Anna Krichevsky, PhD, of Brigham and Women’s Hospital, discussed her work in system analysis of microRNA signaling pathways and survival of GBM patients.

— Ingo Mellinghof, MD, of Memorial-Sloan Kettering Cancer Center, talked about his group’s systems biology approach to developing PET imaging radio tracers to identify mutations in glioma.

— Brent Reynolds, PhD, of the University of Florida, discussed his group’s application for studying complex adaptive systems and managing tumor populations.

After the presentations, NBTS and the researchers decided to take six more months for the research to mature and then open up the process for deciding which teams would go forward with the second, more extensive phase of the Mary Catherine Calisto Systems Biology Initiative.

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