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Joint research team finds key to treating multiple cancers

The newly discovered compound blocks the pathway responsible for tumor formation

A joint effort by researchers at the University along with those at Indiana University, the University of Colorado and Yale University, has led to the discovery of a compound capable of inhibiting a key step in the growth of cancer tumors. This discovery may lead to novel therapies for lung, bladder, prostate, colon and pancreas cancers — most of which were not previously known to be related.

The key factor is the signaling protein, Ral, which acts as an on-off switch for the Ras pathway, a chain reaction that results in tumor-causing mutations. The Ras pathway is critical to a large number of cancers and was originally discovered in bladder cancer research by Dr. Dan Theodorescu, director of the NCI designated Comprehensive Cancer Center at the University of Colorado.

“I think it's going to have — if we are able to block the invasions — very significant ramifications,” Theodorescu said. “The protein Ral is important in pancreatic [cancer], bladder cancer, … a number of the cancers that are driven by the the protein.”

Center for Cell Signaling Director David Brautigan, who worked with Theodorescu, said the research is particularly important for bladder cancer research.

“[Bladder cancer is] one of the underserved tumors — it impacts a lot of people, and it’s one of those things that doesn’t get a lot of press coverage or attention or research dollars,” Brautigan said. “And so Dan has really made bladder cancer the center of his entire research career.”

The team initially studied the pathway hoping to find a means of stopping metastatic bladder cancer — a cancer that starts in the bladder but soon spreads elsewhere in the body. The discovery that the pathway caused metastasis came from analyzing multiple studies, including genetic analysis lead by the NIH.

Once the pathway was discovered, the challenge became finding a molecule small enough to bind to Ral, which is in itself a very small protein. According to Brautigan, scientists have known that Ral was a target for about 20 years.

“It’s basically a small protein that switches between two states,” Brautigan said. “And it functions as a switch, to switch on the growth of the tumor. So the challenge was, how do you get a small molecule that stops a small protein from switching between the two states.”

The process started with a structural biologist at the University of Indiana, who created a computer model of the Ral protein and tested 500,000 small virtual molecules, to see which ones would bind to Ral when it was switched “off.”

“It depended on the work of structural biologists, computer scientists and biochemists — people who wrote the algorithms,” Brautigan said. “It’s people that you wouldn’t otherwise think are cancer researchers.”

The University team, Theodorescu, Brautigan and Yale Prof. Martin Schwartz, then had a much shorter list of molecules they knew would bind to Ral. They then tested for their effectiveness in stopping the protein from switching to its “on” state. They reduced the list of possible candidates from about 200 to 12.

Those compounds were administered as drugs, and their ability to shrink human bladder tumors grown in mice was measured.

The compound found to work best, RBC10, was then passed along to NantBioScience, a California-based pharmaceutical company working to create a “targeted therapy” drug that will administer the compound directly to the Ral molecule.

Though this research is focused on treating cancer once it has manifested, Brautigan said it is even more important to take preventative measures.

“Smoking turns out to be the huge, dominant risk factor for bladder cancer,” Brautigan said. “You stop and think, ‘Yeah, it’s not just everything you eat.’ All those noxious chemicals end up passing through the urine, and so they get into the bladder.”

Researchers hope this new discovery will eventually slow down if not stop solid tumor cancers developed by mutations of Ras.

“In cancer the genetics really determine the cancer you have,” Theodorescu said. “Not every single tumor cancer will be driven by the Ral protein, … it will help the ones that are.”

—Urvi Singhania contributed to reporting on this story.

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