For Immediate Release
April 19, 2009

BUFFALO, NY - William Cance, MD, Chair of Surgical Oncology, Roswell Park Cancer Institute (RPCI) will present “A Small-Molecule Inhibitor, Targeting FAK and Mdm-2 Interaction, Blocks Breast and Colon Tumorigenesis in vivo” at the American Association Cancer Research (AACR) 100th Annual Meeting, 2009, April 18 - 22 in Denver CO.

When protein meets protein at the boundary of a cell, life-and-death messages are transmitted. Normally, interactions between incoming regulatory protein molecules and the cell’s receptor molecules dictate cell growth and other healthy activities. But regulatory proteins can run wild, triggering the uncontrolled cell growth we call cancer.

By concentrating on the points where regulator and receptor molecules connect, rather than on entire proteins, and by adopting a novel, fast-track strategy for finding a drug to block that connection, researchers at Roswell Park Cancer Institute (RPCI) have identified a compound that stops the spread of breast and colon cancers.

Dr. William Cance, who leads the team, explains: “The accepted lore says that the interface between proteins is very difficult to target.” Dr. Cance holds the Chair of Surgical Oncology at RPCI, where his research focuses on focal adhesion kinase (FAK), a protein that regulates normal cell activity but can become “overexpressed” and encourage cancer growth.

“FAK and Mdm2” — a receptor protein —“are critical to the process,” he says. Earlier research had associated interactions between them with breast and colon cancer. “We realized that if we could keep them apart—stop them from interacting—we might be able to force cells to behave normally. So we went looking for the ‘docking sites’ where the molecules bind, rather than trying to knock out the entire molecules.”

Tiny as they are, protein molecules are complex and precisely constructed. When they interact, they align so that a specific site on one binds to a specific site on the other. Dr. Cance explains, “You’ve seen footage of a space shuttle orienting itself as it approaches the International Space Station. They can connect only when the shuttle’s docking assembly lines up exactly with the port on the space station. And if there’s already another spacecraft in the port,” he says, “the shuttle can’t dock.”

By studying computational models of FAK and Mdm2, the team identified the locations and, importantly, the shapes of the binding sites. Shape matters, since one molecule fits into a “pocket” in the other as specifically as a key fits a lock.

The shape of the Mdm2 docking site gave the team one clue to the FAK-blocking molecule they were looking for. The ideal compound would also have to be effective when taken orally, a characteristic that simulations can identify.

Going back to the computers, they consulted a National Cancer Institute database of “small molecule” compounds—druglike substances that do not usually occur in the human body. “We screened models of more than 140,000 compounds, looking for molecules that could dock with Mdm2,” Dr. Cance says.

“The news is that we did all of this in silica. We were able to sit back and let the computer run a high-throughput screening, simulating each compound in as many as a hundred different conformations to see whether it could bind into our site.”

Traditionally, researchers distinguish between experiments done in vitro—in lab ware—and those performed in vivo—with living creatures. As computation has become an indispensable tool, the term in silica has emerged to describe simulations that run on silicon chips.

The screening narrowed the field to 24 candidates. Then the team went hands-on, taking tangible samples of the compounds into the lab and testing each one on live breast, melanoma, colon and pancreatic cancer cells. One compound, M13, significantly decreased cancer viability. “Subsequently,” Dr. Cance says. “tests on laboratory models confirmed that M13 does block breast and colon cancer tumor formation. So the data suggests that targeting the interaction between proteins can lead to effective therapies.’

The research, which began at the University of Florida, was funded by the National Cancer Institute. “The attraction of working at Roswell Park is its incredible translational science,” says Dr. Cance. “We have natural collaborators, scientists and clinicians to take our work from lab bench to bedside. Without the technologies—and the people—that enabled us to see where and how proteins interact, we could never have identified M13 this quickly.”

Roswell Park Cancer Institute, founded in 1898, is the nation’s first cancer research, treatment and education center and is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers. Roswell Park has affiliate sites and collaborative programs in New York, Pennsylvania, and in China. For more information, visit RPCI’s website at www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or e-mail askrpci@roswellpark.org.

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