Dengue and Ebola viruses have very little in common, but Stanford-led researchers have discovered one vulnerability that they share: They can be inhibited by combining the cancer drugs Tarceva (erlotinib) and Sutent (sunitinib).
The cancer drugs work by inhibiting two enzymes that normally work to facilitate the spread of the viruses among cells. Neither enzyme was the primary target of Tarceva or Sutent—the researchers discovered the drugs’ ancillary effects by scouring public databases. But they knew they were on the right track when they showed in a lab dish that the combo was effective against hepatitis C, according to a press release. So they tested the cancer drugs in mouse models of dengue and Ebola. Their results were published in the Journal of Clinical Investigation.
In the study, the Stanford-led team described the mechanism that Tarceva and Sutent use to disable viruses—an approach that they believe could be effective against many different infectious diseases. The enzymes they inhibit, called AAK1 and GAK, alter the molecular makeup of cells in a way that causes them to bind more tightly to viruses. Blocking the enzymes cripples the viral infection.
Because this approach disables proteins within the host cell, rather than attacking the specific viruses directly, the researchers believe it can be applied to many different types of viruses. Ebola and dengue are what’s known as RNA viruses, because their genetic makeup consists of RNA instead of DNA. Hepatitis C is an RNA virus, as are Zika and West Nile, and the research team has shown that Tarceva and Sutent are also effective against those viruses when tested in a lab dish.
"We've shown that a single combination of drugs can be effective across a broad range of viruses—even when those viruses hail from widely separated branches of the evolutionary tree," said senior author Shirit Einav, assistant professor of infectious diseases and of microbiology and immunology at Stanford.
When the combination of cancer drugs was administered to mice infected with dengue, more than 65% of the animals survived, vs. none of the control animals. Even if the cancer drugs were given 48 hours after infection, they remained effective, according to the release. When tested in mice with Ebola, half the animals survived.
Conquering viruses by interrupting the cellular machinery on which they depend is a popular research tactic. Scientists at the University of Pennsylvania, for example, have shown that by blocking a calcium-signaling pathway inside cells, they can slow down the ability of viruses to exit their host cells and spread. In 2015, a Penn team demonstrated the potential of this technique in Ebola as well as in the viruses Marburg, Lassa and Junin.
Although the Ebola outbreak in Africa was eventually brought under control, the demand for treatments and vaccines continues worldwide for it and other RNA viruses. Dengue infects about 390 million people per year, and while Sanofi got the first vaccine on the market last year, pickup has been slow. Other efforts to combat the disease are ongoing, but it’s challenging: There are four different strains of dengue, making its victims vulnerable to re-infection from a different strain later in life.
Drug resistance is an ongoing concern with cancer treatments such as Tarceva and Sutent. So the Stanford team did some additional lab experiments to see if the dengue virus could build up resistance the drugs. Those experiments confirmed the value of attacking the cell machinery rather than the virus itself, Einav said.
Why? Because the virus remains dependent on AAK1 and GAK, no matter how it mutates.