Thanks to research by a Duke professor, drugs that have been employed in clinical trials against cancer have found a second use in treating life-threatening malaria symptoms.
With funding for malaria research relatively low and the severity of the disease high, developing new drugs is often a challenge. But by finding an alternate use for an existing drug, researchers are able to save both money and time—and take steps toward saving lives.
"The need for new anti-malarial drugs is immediate, and one of the problems is that to get a drug approved, there are safety tests and efficacy tests you have to go through, and all of those take time,” said Jon Clardy, co-author of the study and professor of chemical biology and molecular pharmacology at Harvard University.
The findings—which will be published in an upcoming edition of research journal ChemBioChem—were part of a research endeavor between Clardy and Emily Derbyshire, lead author of the study and assistant professor of chemistry.
Their efforts were part of a response to malaria parasites that are developing resistance to current anti-malarial drugs. Researchers screened various drugs—all from a class known as protein kinase inhibitors—for their ability to interfere with the malaria parasite’s ability to spread within the body. Along the way, the scientists noted that the kinases have an important role in cancer cells.
“All of these [malaria-fighting] compounds were initially selected for an ability to bind protein kinases in humans,” Derbyshire said. “When cancer cells proliferate, some of these kinases are shown to be very important."
Protein kinase inhibitors—which Derbyshire views as "magic bullets"—can shut down kinase proteins within malaria that are important in cellular signaling. This prevents the parasite from rapidly spreading from the liver before infecting and bursting red blood cells.
“A big problem with malaria parasites is that they can rapidly mutate…once a drug has been introduced into the market, within weeks to months you can see strains in people that are no longer affected by the drug,” Derbyshire explained.
Derbyshire added that the drugs they researched can hit multiple targets within malaria, making it much more difficult for the parasite to develop resistance.
Despite the severity of malaria and its developing resistance to current drugs and treatments, funding for research remains an issue. Drug research and development is focused on other prevalent diseases, such as cancer, that are seen as more of an immediate threat to the American public, Derbyshire said.
“If you can start with an approved drug, then a lot of safety issues are taken care of, so one of the strategies that people are employing is what they are calling ‘repurposing,’ where you take a drug that’s approved or almost approved and try to use it for different applications,” Clardy said.
He explained that because resources are so limited for malaria research, it is better to investigate drugs that have already been developed for other uses. A wealth of research has already been done on cancer drugs, making it easier and faster to start with examining existing drugs rather than creating new drugs altogether.
Clardy said his lab is collaborating with the Medicines for Malaria Venture—funded by both the Gates Foundation and the World Health Organization—to develop, test and deploy the drugs.
He added that drug development is expensive and resource-intensive and the current drugs are nowhere close to ready for the market.
“It would be very premature to be talking about any of these things being used on people in the near future,” Clardy said.
Timothy Haystead, associate professor of pharmacology and cancer biology and associate professor of pathology, explained that the malaria parasite is constantly evolving to avoid immune system response by its hosts. For example, the drug chloroquine has traditionally been used as a defense against malaria in other countries, but its efficacy has greatly decreased in recent years due to inappropriate overuse that has led to resistance, he said.
“The nice thing about chloroquine was that it was cheap, you took it once a week, so it was very effective and actually had, post-World War Two all the way to 80’s, a major impact on holding back the disease,” Haystead said. “They used to put it in table salt in South America, which ended up contributing to its resistance.”
Haystead said he believes that a new multi-target drug, which could be created from Derbyshire’s findings, will be much more effective in fighting malaria than vaccination efforts. In order to eradicate malaria, he said, vaccines must be able to immunize 100 percent of all people living in malaria-infested regions. But the region of DNA that generates malaria’s surface receptors—which are what vaccines target—are highly susceptible to mutations that confer resistance to the malaria parasites.
“A lot of people are starting to go back to the idea of drugs because it’s been drugs, not vaccines, that have really controlled the disease,” Haystead noted.
Haystead said that any potential drug’s implementation would also have to overcome serious challenges, including political problems such as war and corruption.
“Drug resistance and trying to offset it from the beginning and trying to make things that would inherently prevent development of resistance—if we put [malaria] under drug pressure or use those drugs inappropriately without combination, then we’ll get resistance,” Haystead said. “But if you can build it to make it more robust in the beginning, then…it might just be exactly the magic bullet.”
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