November 13, 2014 | by City of Hope
Chemotherapy drugs work by either killing cancer cells or by stopping them from multiplying, that is, dividing. Some of the more powerful drugs used to treat cancer do their job by interfering with the cancer cells’ DNA and RNA growth, preventing them from copying themselves and dividing.
Such drugs, however, like Hydroxyurea, do have drawbacks. One is that the body metabolizes them quickly. Patients need frequent doses to achieve the desired effects. Because the side effects of the drugs are already considerable, increased use of them raises the risk of negative reactions. Another drawback is that cancer cells develop rapid resistance to the drugs, reducing their effectiveness.
A team effort
As a physician, molecular pharmacologist Yun Yen, M.D., Ph.D., knows well the limitations of chemotherapy drugs. He partnered with medicinal chemist David Horne, Ph.D., to find — and improve — a molecule, or compound, to overcome these problems.
First, Yen selected a promising anti-cancer compound from the National Cancer Institute’s library of anti-cancer agents. Then, using data obtained with the help of the skilled laboratory scientists in City of Hope’s Core (or “Shared”) Services, Horne began to make structural adjustments to improve the molecule’s effectiveness. Core Services provides researchers, specialized expertise, testing and instrumentation in fields such as molecular modeling, screening, medicinal chemistry and cancer biology. Access to these services enabled Yen and Horne to determine, even before preclinical testing, how the compound worked.
Working with a multidisciplinary team through long cycles of chemical adjustment, testing and more adjustment, Yen and Horne were able to build a better cancer drug, COH29. Having these resources on-site made this labor-intensive process affordable. As Horne says, “COH29 is not easy to synthesize. Contracting production would have been three, even four times the cost.”
In preclinical studies, COH29 has been shown to reduce tumor growth in human cancers. It has proved most effective against leukemia and ovarian cancer — diseases that are hard to treat, and for which new approaches are desperately needed. Further, it has also shown promise against breast cancer cells.
It could only happen here
Not all institutions have medicinal chemists on staff, requiring outside collaborations and a lengthy development time for refinement of compounds. Horne came to City of Hope in 2007 specifically to launch what’s known as the small molecule program and to develop treatments like COH29.
Having affordable and accessible Core Services on campus spares clinicians and researchers like Yen from having to acquire equipment — and the experts who know how to use it — for their own labs.
Yen credits City of Hope’s supportive and “collegial” environment for helping to get the drug to trial in a third of the time one might expect. “The know-how is already there,” he says. Having expert resources on campus — including help with Food and Drug Administration (FDA) filings, which can run to 1,000 pages — allowed the team to focus on developing the drug without getting bogged down.
COH29 was the first small molecule to be produced in the Chemical GMP Synthesis Facility. In addition to saving costs and time, and assuring high quality, manufacturing on campus enables City of Hope to retain the patent for the drug. Future royalties, then, can help fund further research.
Moving beyond the city
Taking compounds like COH29 to clinical trial is usually the domain of pharmaceutical companies. However, following a review this summer by the FDA, a phase I, first-in-human trial of COH29 will likely begin at City of Hope in late 2014. A new lot of the drug for the trial is currently being manufactured at the Chemical GMP Synthesis Facility. The long-term goal is to develop it into a new therapy for ovarian cancer.
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