Physicians have used the same drug — hydroxyurea — to treat leukemia, melanoma and other cancers for about 60 years. Now, a collaborative team of City of Hope researchers is developing a new targeted therapy that might replace this aging standard of treatment. The National Cancer Institute (NCI) recently awarded City of Hope researchers a 5-year, $1.7 million grant to develop a novel drug that does the same job as hydroxyurea — only better. The team is led by Yun Yen, M.D., Ph.D., the Dr. & Mrs. Allen Y. Chao Chair in Developmental Cancer Therapeutics and associate director of translational research in the cancer center.
Hydroxyurea blocks an enzyme called ribonucleotide reductase, which makes the building blocks of DNA. Cancer cells grow rapidly and need large amounts of these building blocks to make enough DNA to keep up with their growth. Because of this, cancer cells have a lot of ribonucleotide reductase — much more than normal cells.
|Yun Yen (Photo by Kaminsky Productions)|
Because cancer cells make so much more ribonucleotide reductase than healthy cells, the enzyme is a good candidate for targeted therapies, said Yen. A targeted drug that blocks the enzyme would strongly affect cancer cells but would leave normal cells alone.
Hydroxyurea, while good at blocking ribonucleotide reductase, has shortcomings — it quickly becomes inactive in the body, and cancer cells usually become resistant to it, according to Yen. And because it is not a targeted therapy, it also can cause debilitating side effects, including vomiting, diarrhea, inflammation of the mouth that can hamper eating and drinking, and bone marrow suppression, which can lead to lifethreatening infections and severe anemia.
Despite the side effects, hydroxyurea is the only ribonucleotide reductase inhibitor approved by the Food and Drug Administration, so it has remained a staple of cancer treatment for decades.
Now the City of Hope team has created a new compound, dubbed COH20, that Yen believes could eventually replace hydroxyurea as a better choice for treatment.
“Our compound has a totally different mechanism from hydroxyurea,” he said. The drug should avoid strong side effects while remaining active in the body longer, he explained.
To develop COH20, Yen and his project team began with a computer model that predicted the best target site on the ribonucleotide reductase molecule: the best “button” for a potential drug to push. His team then screened thousands of compounds in the NCI’s database of investigational drugs to find one likely to hit the target.
Yen’s project team consists of David Horne, Ph.D., chair of the Department of Molecular Medicine and co-director of the Synthetic and Biopolymer Chemistry Core, Richard Yip, Ph.D., director of the High Throughput Screening Core Facility, and Yate-Ching Yuan, Ph.D., director of the Biomedical Informatics Core.
To make it more effective at blocking ribonucleotide reductase, Horne made chemical changes to the compound, while Yip checked to see how each change affected the compound’s ability to hit the desired molecular target. Yuan then used computational methods to determine which chemical changes increased the compound’s ability to kill cancer cells. Their combined efforts spawned COH20 — as well as the NCI grant that will further propel its development as a cancer drug.
Yen, who co-leads City of Hope Comprehensive Cancer Center’s Developmental Cancer Therapeutics Program with Richard Jove, Ph.D., director of Beckman Research Institute, says the grant to develop COH20 validates strategic efforts to build a drug-discovery program.
“About three years ago, when Rich came, we discussed how to make a successful drug discovery program,” said Yen. “We took the strategy of assembling multidisciplinary project teams centered around molecular targets like ribonucleotide reductase. This award is a result of all the planning and efforts based on the team strategy.”
Yen and Jove look forward to seeing more new drugs developed using this collaborative project team approach.
“Dr. Yen’s NCI grant success sets the stage for other scientists who are interested in developing novel drugs,” Jove said. “We now have the expertise and facilities in place to effectively do this with collaborative multidisciplinary project teams.”