From a cotton seed to a potential cancer drug

Liang Xu, Ph.D., KU Cancer Center Drug Discovery, Delivery and Experimental Therapeutics Research Program member, associate professor of Radiation Oncology at the University of Kansas Medical Center and associate professor of Molecular Biosciences at The University of Kansas, is looking at the protein Musashi, which is overexpressed in many types of cancer, but especially in colorectal cancer. It is thought that the increased presence of Mushashi causes abnormal cells to divide and tumors to start growing. It also appears to play a role in cancer stem cells that can divide endlessly into cancer cells in all parts of the body.

"It seems to be important in cancer stem cells, which initiate the cancer process, making it all the more important to find a drug for," said Dr. Xu. "We also think recurring cancers are caused by these cancer stem cells hiding and coming back months or years later."

Dr. Xu is looking at a potential natural therapy to block Musashi from encouraging cancer cells to divide, along with the miniscule processes that allow Musashi to flourish.

"The most successful recent cancer drugs block the actions of specific proteins," said Dr. Xu. "They're very specific and very powerful. But we don't have enough drugs that work like that, especially for colon cancer."

His team is working alongside the lab of Kristi Neufeld, Ph.D., co-leader of KU Cancer Center's Cancer Biology Research Program. Dr. Neufeld's lab also studies Musashi, particularly how it interacts with APC, another tumor suppressor protein. She's found that APC helps to regulate Musashi and prevents it from being overexpressed. This starts a trickle down effect of stopping the tumor-stimulating pathways of Wnt and Notch (which encourage cancer cell multiplication) from being activated.

"APC not only inhibits Musashi, but Musashi inhibits APC, so these two proteins seem to have this double negative where they're trying to keep the other one from functioning," said Dr. Neufeld. "So you can think of Musashi as potentially being oncogenic -- too much of it will promote tumors because it's overpowering proteins like APC and triggering those pathways that promote uncontrolled cell growth."

The two labs are collaborating to uncover inhibitors of Musashi that could be turned into drug compounds. It is difficult as its interactions involve RNA-binding proteins that require very specific drugs to inactivate them.

In a recent paper in Molecular Oncology, Drs. Xu and Neufeld appear to have identified a potential drug that's a byproduct of cotton. Dr. Xu, along with the rest of KU Cancer Center's Drug Discovery, Delivery and Experimental Therapeutics Research Program, is taking a closer look at gossypol, a natural component found in the cotton plant. The compound is currently going through early phase clinical trials for prostate cancer.

"A lot of cancers, involve protein and protein interaction, which is like shaking hands with someone," explains Dr. Xu. "This is a very broad interaction, especially when you want to find something small that will block the two hands from shaking, so to speak.

"Musashi, however, is an RNA-binding protein, which is like a hand trying to grab a string. A much smaller target for which it is much more difficult to design a drug."

Further experiments by Dr. Xu's team have uncovered that gossypol directly interacts with the RNA binding pocket of Musashi. This means it directly targets Musashi, an important characteristic in developing new cancer drugs. If the drug targets the protein that's specifically causing cancer, it can rid the body of those abnormal cells without causing too much collateral damage to healthy cells nearby.

To figure this out, Dr. Xu used fluorescence polarization competition assay, which measures how much a target (ex: Musashi) is functioning or present. He discovered that gossypol had a strong binding with Musashi.

Gossypol works by stopping cells from dividing, as well as inducing abnormal cell death in colon cancer cells. When gossypol binds to Musashi, it stops Notch and Wnt signaling in multiple types of colon cancer. All of these functions are key to stopping cancer from starting or spreading.

Though gossypol is still years away from clinical testing in colon cancer, Dr. Xu is heartened by the results he's obtained in the lab so far. Drugs derived from natural compounds usually don't take as long to get FDA approval and are generally safer.

"This is the first drug that appears to target a RNA-binding protein in a successful way," said Dr. Xu. "If we can create a drug that people can take to block this protein and stop cancer from starting or recurring, it would be an ideal situation for patients."