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Inspired by toxins that occur in nature, St. Jude scientists create an entirely new class of drugs that attack cancer in a novel way.
Sometimes inspiration truly comes from above. (Remember Sir Isaac Newton and the apple?) A couple of years ago, falling debris caused much more than a mere bump on the head for another scientist. But the result was, as in Newton’s case, a discovery of some gravity.
When ceiling repairs caused a powdery fungus to sift down onto his head, Thomas Webb, PhD, suffered a violent allergic reaction that resulted in a case of hives and a round of steroids. While he recovered, the researcher began to contemplate the natural toxins that had attacked his system with such vengeance.
“How can I direct that kind of effect against cancer?” pondered Webb, a faculty member in Chemical Biology and Therapeutics at St. Jude Children’s Research Hospital.
Examining natural toxins from organisms such as fungi and bacteria, Webb soon noticed a set of structures that displayed extremely potent biological activity.
“There’s something really special about these molecules,” he told himself. “Nature’s trying to tell me something. I just have to figure out what it is.”
That’s exactly what he did.
He and his colleagues set about designing a new type of anti-cancer drug based on a chemical that bacteria use to attack organisms they infect.
Webb soon became enthralled by the structure of two kinds of natural products: One was a potent anti-cancer compound called FR901464; the other was a type of cancer cell inhibitor called a pladienolide (pronounced play-die-EEN-o-lide). Bacteria use the same mechanism in both of these products to cause harm to other organisms.
The compounds inhibit cancer cells by impeding the function of an enzyme complex called the spliceosome. If the spliceosome cannot fulfill its duties, cancer cells cannot replicate. Webb and his colleagues began creating FR901464 analogs that would prevent spliceosomes from doing their job—thus halting cancer growth.
Instead of using these compounds as they occur in nature, the St. Jude team opted to simplify the compounds’ molecular structures to make them easier to synthesize in the laboratory. Webb and his team identified the molecules’ critical features and began synthesizing new compounds that would be much more active against cancer than the original pladienolides were. Not only are the new molecules simple in structure, but they can also be assembled quickly from inexpensive and readily available chemicals.
Webb attributes the project’s success to an alliance among several talented St. Jude scientists. For instance, Chandraiah Lagisetti, PhD, of Chemical Biology and Therapeutics completed the compounds’ chemical synthesis. Stephan Morris, MD, of the St. Jude Pathology and Oncology departments chose the tumor lines that should be screened so that the team could identify which kinds of cancer were most sensitive to the compounds. Alan Pourpak, PhD, a postdoctoral fellow in Pathology, conducted much of the screening and worked with the project’s laboratory models. A report on their research subsequently appeared in the Journal of Medicinal Chemistry.
The compounds the team created have shown great promise against lung, colorectal, breast, prostate, ovarian and lymph node cancers. The scientists also discovered that one of the new compounds kills cancer cells without causing toxicity.
“After five days of treatment, the tumors go away,” Webb says. “If you have given a sufficient dose, none of the tumors regrow. If this translates into treatment for kids, then it will be beautiful. You’re not talking about agonizing months of treatment with conventional chemotherapy. You’re talking about a relatively short period of treatment for certain tumors. Then the children would return home cured.”
Webb says that this work could lead to an entirely new class of drugs that attack cancer in a manner unlike any current anti-cancer treatments.
“This could be a real breakthrough area,” he says. “St. Jude clinicians are looking for better drugs. They can only do so much with the tools they have. Researchers at St. Jude can change the world in a really positive way by putting the right tools in the hands of the clinicians and saving kids.”
Webb dreams of the day when St. Jude might partner with a pharmaceutical company to develop one of the new compounds for adults as well as kids, using a strategy proposed by Webb’s department chair, Kip Guy, PhD.
“Such a partnership would be a win-win for everyone,” Guy predicts. “St. Jude could maintain all pediatric use of the compound and the pharmaceutical company could have all the adult applications.”
A self-proclaimed optimist, Webb has high hopes for the research.
“I’m determined to develop new drugs that are going to save people’s lives,” he asserts. “Our research is going to save kids’ lives, and when it comes to the point of making an arrangement with a pharmaceutical partner that will help us to develop it, it’s also going to save adult lives. That’s the kind of impact that I’m excited to make.”
Reprinted from Promise Spring 2009
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