August 3, 2007

SPORE renewal boosts GI cancer research

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GI SPORE co-directors Robert Coffey Jr., M.D., left, and Mace Rothenberg, M.D. (photo by Susan Urmy)

SPORE renewal boosts GI cancer research

The Vanderbilt-Ingram Cancer Center has landed another round of support for its Specialized Program of Research Excellence (SPORE) in gastrointestinal cancer, one of only five such programs in the country.

The National Cancer Institute will provide $11.8 million over the next five years to forward Vanderbilt-Ingram's innovative colorectal cancer research.

“We received the top score in the country in the latest pool of GI SPORE applications,” said Robert Coffey Jr., M.D., director of the GI SPORE. “This reflects that we have one of the premier GI cancer programs in the country here at Vanderbilt.”

The NCI established organ-specific SPOREs in 1992 to promote interdisciplinary research with a “translational” emphasis — work that spans the gap from basic science discovery to clinical application. SPOREs bring together basic, clinical and population-based scientists to collaborate on research with clear potential to improve patient care. GI SPOREs are located at Vanderbilt, Johns Hopkins University, Harvard University, the University of Arizona and the University of North Carolina at Chapel Hill.

Vanderbilt-Ingram has two additional SPOREs, one in breast cancer and one in lung cancer. It is one of only seven centers to hold three or more SPORE grants.

Vanderbilt's GI SPORE, co-directed by Mace Rothenberg, M.D., focuses on colorectal cancer, the second leading cancer killer in the United States.

There will be nearly 150,000 new cases of colorectal cancer diagnosed this year and more than 55,000 deaths, according to American Cancer Society estimates. And because the risk of developing colorectal cancer grows with age, the impact of this cancer is expected to increase as the U.S. population ages.

Coffey attributes Vanderbilt's success in colorectal cancer research to a “very strong three-pronged approach.” One prong, the Epithelial Biology Program, focuses on polarized colorectal cancer cells in vitro — how they compartmentalize important signaling molecules like the epidermal growth factor (EGF) receptor and some of its ligands. Insights from cells are advanced to mouse models in the second prong — Vanderbilt is a member of the NCI's Mouse Models of Human Cancers Consortium (MMHCC) — and to human beings studied as part of the GI SPORE in the third prong. Coffey is the only person in the country to direct both an MMHCC and a SPORE grant.

“We have created a robust platform to propel forward innovative diagnostic and therapeutic approaches to colorectal cancer,” Coffey said.

In the GI SPORE's first five-year cycle, Vanderbilt investigators made significant progress, Coffey noted. They implicated altered regulation of p120 — a protein first identified at Vanderbilt — in the pathogenesis of colorectal cancer, conducted a biomarker-based cooperative group trial of Iressa in the treatment of advanced colorectal cancer, and initiated a large population-based study examining predictors of adenoma (colon polyp) recurrence.

The renewal application for the GI SPORE includes continuing projects from the first cycle and a new high-throughput screening strategy that aims to develop drug candidates for treating colorectal cancer.

“We knew that the competition was going to be intense, so we decided to 'roll the dice' and propose high-risk, high-payoff projects,” Coffey said. “We are the first SPORE to propose high-throughput screening.”

The investigators are using the Vanderbilt Institute of Chemical Biology's high-throughput screening facility under the direction of C. David Weaver, Ph.D., to screen libraries of synthetic small molecules and natural products. R. Daniel Beauchamp, M.D., is leading a screen for compounds that restore E-cadherin to the cell surface of colorectal cells and could therefore reverse the epithelial-to-mesenchymal transition that is a central event in the development of metastasis. Ethan Lee, M.D., Ph.D., is directing a screen to identify agents that block Wnt signaling, a pathway that becomes deranged in nearly 90 percent of colorectal cancers.

“We already have a number of exciting hits from these screens,” Coffey said. One of the “hits” is an FDA-approved drug that “has the potential to advance rapidly to a clinical trial.”

A new feature of Vanderbilt's GI SPORE renewal application was the inclusion of patient advocates as integral members of each project.

“We're very proud that we have a strong group of patient advocates who are an integral part of our SPORE program,” Coffey said.

“They are always reminding us…how is this going to impact patients with colorectal cancer, either in terms of prevention, diagnosis or treatment. That's a good reality test.

“I think we're uniquely poised to make significant advances in these areas over the next five years.”

GI SPORE projects and their leaders

Project 1 will implement optimum clinical blockade of the EGF receptor axis and Src inhibition. (Coffey, Rothenberg and Jordan Berlin, M.D.)

Project 2 is the high-throughput screening directed against the targets E-cadherin and axin. (Beauchamp and Lee)

Project 3 will pursue the role of p120 in the pathogenesis of colorectal cancer. This continuing project builds on major findings during the first SPORE funding cycle about p120's role in regulating E-cadherin and in early steps in the development of colorectal cancer. (Albert Reynolds, Ph.D., and Mary Kay Washington, M.D., Ph.D.)

Project 4 continues the Tennessee Colorectal Polyp Study, an effort to identify predictors for adenoma incidence and recurrence. Molecular and lifestyle predictors will aid colorectal cancer prevention efforts. This project dovetails with the Jim Ayers Institute for Precancer Detection and Diagnosis at Vanderbilt, directed by Dan Liebler, Ph.D., which aims to identify a serum marker for colorectal cancer. (Reid Ness, M.D., M.P.H., and Wei Zheng, M.D., Ph.D., M.P.H.)

The SPORE is supported by a number of “tremendous cores,” Coffey said. These cores and their leaders are Administrative, Coffey, Rothenberg and Ann Greene; Tissue, Washington; Clinical Trials, Rothenberg; Biostatistics, Yu Shyr, Ph.D., and Bonnie LaFleur, Ph.D., M.P.H.; and High-Throughput Screening, Weaver, Michelle Lewis, Ph.D., and Emily Days.

“I can't emphasize enough how much of a team effort this was,” Coffey said. “This renewal represents the tireless efforts of people like Jeffrey Franklin, Bonnie LaFleur and H. Charles Manning, who are really the unsung heroes of this process. They are three examples of the willingness of people to pull together and work toward a common goal, which is, I think, one of the real strengths of Vanderbilt.”