October 22, 2004

$12.5M will fund cancer forecasting effort

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Vito Quaranta, M.D., professor of Cancer Biology, is leading a new effort to create mathematical models of cancer invasion. (photo by Dana Johnson)

$12.5M will fund cancer forecasting effort

Vito Quaranta, M.D., is looking forward to the day when predicting a tumor's clinical progression will be as methodical as forecasting the weather.

Quaranta and a group of colleagues at Vanderbilt University and the University of Dundee in Scotland have been awarded a five-year, $12.5 million grant from the National Cancer Institute to develop mathematical models of cancer invasion. The investigators hope that these models will serve as tools to guide patient treatment and predict prognosis, since invasion and metastasis are what make cancer a life-threatening disease.

Vanderbilt is one of nine specialized centers in the new Integrative Cancer Biology Program (ICBP), an NCI initiative which aims to apply a multidisciplinary systems-based approach to build predictive cancer models.

“Today we can know pretty well that for the next few days we're going to expect good weather or that there's a storm on the way. That's the kind of predictive power we would like to generate with our model for cancer invasion,” said Quaranta, professor of Cancer Biology.

His vision for future cancer patients goes something like this. The properties of a patient's newly diagnosed tumor are measured, perhaps using mostly non-invasive imaging technologies. The tumor's properties are then entered into a computer program which simulates — using the set of mathematical equations that form the model — how that particular tumor will progress over time.

The simulation results might show that the tumor has a very low propensity to invade, suggesting that the patient needs only periodic evaluations and simulations. Or the results may show that the tumor is of a highly invasive nature, suggesting that the patient needs immediate and long-term aggressive treatment. Today, the tools for making such a distinction perform poorly, Quaranta said, “and we desperately need 'exact' methods.”

It sounds like something out of a “Star Trek” episode, the idea of plugging in numbers and then saying to a computer “simulate cancer progress,” but it's not science fiction, Quaranta said. Mathematical modeling is increasingly being applied to all aspects of biology.

“Biology is undergoing a transition, from a science of accumulating empirical data and attempting to make sense of it to a science in which we can actually develop theories and models and design experiments to test those theories,” he said.

Vanderbilt's investments over the last several years have created an environment in which “big science” can thrive, Quaranta said. That and the institution's collegial atmosphere contributed to the success of the grant proposal.

“Getting this grant is a real feather in our cap, as the competition was fierce,” said Jeffrey R. Balser, M.D., Ph.D., associate vice chancellor for Research. “Vanderbilt is uniquely positioned for efforts such as this given the strength of our Cancer Center and the tremendous investment we've made in trans-disciplinary research and research infrastructure. Our existing, remarkable foundation of cross campus collaboration will serve these investigators well.”

Quaranta, who came to Vanderbilt last year from The Scripps Research Institute in La Jolla, Calif., teamed with Peter T. Cummings, Ph.D., John R. Hall Professor of Chemical Engineering, Alissa M. Weaver, M.D., Ph.D., assistant professor of Cancer Biology, and Alexander Anderson, Ph.D., a biomathematician at the University of Dundee, to develop the proposal. The Biomathematics Study Group, directed by Emmanuele DiBenedetto, Ph.D., Centennial Professor of Mathematics, was key to the effort.

The new center will support efforts of a diverse group of Vanderbilt scientists, among them cancer researchers, oncologists, chemical and biological engineers, theoretical and applied mathematicians, imaging scientists, and computational biologists.

As a starting point for modeling cancer invasion, the project uses Anderson's “hybrid discrete-continuous” model. This model takes into account both physical variables that can be measured, like oxygen concentration, and variables that have random behavior, like cells.

Treating a tumor as a collection of cells, rather than as a solid mass acting as a unit, is key to modeling cancer, Quaranta said.

“Cancer cells behave as if they have minds of their own,” he said. “Three or four side-by-side cancer cells can behave in very different ways because of differences in their genetic make-ups, or differences in how they respond to microenvironment stimuli. The behavior of a group of tumor cells — during invasion, for instance — emerges from the individual behaviors of each cell. Each cell needs to be represented by its own equation, rather than being averaged out.”

In its current version, the model includes four parameters: the number of cells and their rate of growth, the matrix that binds those cells together, enzymes the cells produce to degrade or “chew up” the matrix, and the oxygen concentration.

To move the model closer to reality, the group will add cellular and microenvironment invasion parameters — properties that might affect cancer invasion. These include cell death resistance or sensitivity, cell-cell adhesion, cell migration, metabolism, mutations, and angiogenesis.

As parameters are added, the model will be tested experimentally — in cells growing in the laboratory and in animals — and adjusted to reflect the findings. This cycle of adding, testing, and adjusting will continue “until the model is able to closely predict cancer invasion as it happens in real life: in three dimensions and over time,” Quaranta said. “When that happens, innovative clinical applications will be within reach.”

The new center also will train scientists who are “fluent both in mathematics and biology,” Quaranta added. And as part of the ICBP initiative, the center will share its findings, with the hope that other scientists will participate in testing and improving the group's theory of cancer invasion.

“These are exciting times to be involved in biological research,” Quaranta said.