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    Leading Research in a New Direction

    By Gail Zyla, National Brain Tumor Society

    In 2010, the National Brain Tumor Society (NBTS) launched the largest singular research initiative it has ever undertaken: the Mary Catherine Calisto Systems Biology Initiative. NBTS believes that this is a watershed moment for the brain tumor community. Systems biology is a new approach to brain tumor research that holds promise to increase the speed at which effective new treatments for brain tumors are developed.

    Historically, scientists have tried to understand brain tumors by studying one or two parts of the tumor that had gone awry, such as a gene or protein. While this research has greatly expanded our knowledge of brain tumors, it has had limited success in helping develop new therapies.

    What has emerged is the understanding that brain tumors are highly organized systems. A brain tumor is a “complex network that senses a variety of things that a cell uses to decide whether it should grow or not,” says Lewis Cantley, Ph.D., of Harvard Medical School and Beth Israel Deaconess Medical Center. “We know that hitting a single component in this network is rarely effective in treating cancers.” Systems biology recognizes this quality of brain tumors and focuses on shutting down the entire system – not just one or two parts.

    “Most brain tumor research has studied smaller and smaller components with the idea that by understanding the individual components, you can understand the workings of the whole system,” says Gordon Mills, M.D., Ph.D., chairman of the Department of Systems Biology at MD Anderson Cancer Center in Houston, Texas. “But nothing works in isolation. The parts have to be put into context. What is central to the systems biology approach is that components are not studied in isolation, but rather in the context of interconnecting and interacting systems.”

    Challenges in Developing Treatments

    Certain qualities of brain tumors make them resistant to treatment:

    Diversity: The World Health Organization has identified more than 120 different types of brain tumors. Within these types, there are additional subtypes that have different genes, proteins, and other characteristics. Because of this diversity, a treatment that is effective for one type of brain tumor will not necessarily work on another type. A key focus of systems biology is finding ways to quickly identify the precise combinations of gene mutations and proteins that predict tumor growth, and then designing a personalized treatment plan that will best stop the progress of a particular tumor.

    Adaptability: “Brain tumor cells are incredibly adaptable and incredibly robust,” says Brent Reynolds, Ph.D., of the William L. McKnight Brain Institute at the University of Florida. For example, when faced with a treatment targeted at a problem gene or protein, the cells may be able to change to resist the treatment. In addition, many brain tumor cells can adapt to subtle changes in their environment, making them moving targets for treatments.

    Complexity: The many different components of brain tumors form a sophisticated network that is able to send signals and provide backup when part of the network is affected by treatment. One of the hopes of systems biology is that it can be used to develop computerized models of these networks, designed to predict how the entire tumor system will react when one part of the tumor is treated, or “poked.” Location: Because the brain is the control center for thought, emotion, and movement, any treatment is almost certain to impact at least some aspects of the person’s physical and mental wellbeing. In many cases, the effects of treatment are devastating.

    The blood-brain barrier: The body protects the brain with a cellular barrier that blocks many chemical substances, including toxins, from entering. Any brain tumor treatment must be able to bypass this barrier.

    Innovation through Expert Collaboration

    NBTS is leading the brain tumor community toward systems biology with the $5 million Mary Catherine Calisto Systems Biology Initiative. This research initiative mandates that grantees form a team of scientists that includes experts outside of their own specialties. Each grant will be reviewed by the NBTS Scientific Advisory Council. The reviewers will score the applications based on their scientific merit and then present their findings to the NBTS Board of Directors.

    Grants of up to $100,000 will be given for the first stage of planning, which is focused on developing a collaborative plan and timeline during the first year. Upon review of the Phase I results, three grantees will move on to Phase II. Each will receive $1.5 million over three years ($500,000 per year) to execute the research plan.

    The Promise of the Mary Catherine Calisto Systems Biology Initiative

    • Promote development of more effective therapies and new treatment options for people with brain tumors

    • Lead the brain tumor research community to shift from a traditional approach to systems biology

    • Encourage other funding agencies to invest in systems biology research

    • Bring together experts from a wide variety of disciplines to come up with innovative approaches to treatment

    • Use cutting-edge technologies to develop models of brain tumor systems that will help scientists predict which treatments are best suited to each unique type of brain tumor

    • Increase the speed and efficacy of getting brain tumor research to clinical trials