Cancer drugs an unexpected ally in the battle against malaria

Apr. 1, 2013 In the fight against malaria, cancer drugs are far from being considered a useful tool. But new research at Seattle BioMed reveals that liver cells, which are first infected by Plasmodium parasites after their transmission by mosquito bite, actually behave in similar ways to cancer cells. The work also shows that with the help of cancer drugs, the liver can become a hostile environment for the malaria parasite.

This exciting new development is published in this month's issue of the journal Cell Reports.

Humans get malaria by bites from mosquitoes that carry Plasmodium parasites, the most deadly of which is P. falciparum. In malaria research, mouse malaria parasites are frequently used because, like human parasites, they have a "liver phase," in which the parasite first multiplies in the liver and then breaks out into the blood stream to cause disease.

"We knew the malaria parasite goes to the liver, infects liver cells and replicates within them, but we didn't know how it forces the liver cell into submission on a molecular level," says Alexis Kaushansky, lead author and postdoctoral scientist at Seattle BioMed, describing this key stage to the parasite's infectious abilities as a black box.

Kaushansky's background is in cancer biology, so she decided to draw on her strengths to better understand how liver cells were responding to the malaria parasites when she joined the laboratory of Stefan Kappe, professor and director of the malaria program at Seattle BioMed.

One of the challenges to studying the liver phase of malaria is the sheer paucity of infected cells. The liver is a large organ, and the parasites only infect a few cells -- so isolating these cells to study them is extremely difficult, even in mice. As a graduate student, Kaushansky had used systems biology tools to study cancer signaling, and with collaborators Albert Ye and Gavin MacBeath at Harvard Medical School, worked to develop a protein array technology that enabled her to get a large number of read-outs from the few cells she could isolate. Though the technology had been developed in a cancer lab, she eagerly applied it to her work on malaria.

The study yielded a surprising result: many of the molecular changes that malaria parasites cause in infected liver cells are strikingly similar to changes that happen when normal cells transform into cancer cells. But since a liver cell infected with malaria dies when the parasite leaves, there is no characteristic tumor like in liver cancer.

In particular, the malaria parasite dramatically lowers the activity of p53, a classic "tumor-suppressor" in infected cells. This was exciting, since p53 is thoroughly studied in the cancer field, and many cancer drugs are specifically targeted to increase its activity.

Kaushansky and Kappe administered the small molecule Nutlin-3, originally developed as an anti-cancer compound, to mice infected with liver-stage malaria. The cancer drug dramatically reduced malaria infection in the liver, killing 80-90% of the parasite-infected cells.

Using cancer drugs to prevent malaria potentially addresses a key economic challenge in drug creation. Since a vast majority of people who are afflicted with malaria live on less than two dollars a day, developing new drugs, each of which can cost upwards of a billion dollars, can be daunting to pharmaceutical companies who are trying to satisfy shareholders. However, if a drug that has been developed to treat cancer can also be used to prevent malaria, much of the development cost need only to be paid a single time.

Originally posted here:
Cancer drugs an unexpected ally in the battle against malaria