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Combination of two approved cancer drugs defeats dengue, Ebola viruses in mice

Ebola virusTreating viral infections with a "one drug, one bug" approach can be quite successful, as in the case of hepatitis C. A concerted effort generated several approved -- and extremely effective -- antiviral treatments for that disease.

But it also took more than 10 years of research and ran up costs exceeding $2 billion, says Stanford virologist and drug developer Shirit Einav, MD -- hardly a selling point for drug companies thinking about developing antivirals to combat diseases that occur almost exclusively in the developing world. (Dengue, Ebola, Zika and West Nile come to mind.)

Making matters worse is the impossibility of predicting what the next emerging viral threat will look like, says Einav.

“We’re always getting blindsided,” she told me.

So, in a study just published in the Journal of Clinical Investigation, Einav and her colleagues stole a march on the pint-sized parasites, who -- putting it politely -- "repurpose" our cellular machinery and get it to do their bidding. The researchers repurposed a couple of approved cancer drugs and put them to work fighting viral infections.

The investigators' approach marks a huge departure from the typical virus-fighting paradigm: Rather than attack some component of the virus itself, what if we temporarily disable a feature of our own cells that the virus desperately needs in order to successfully infect us?

I explain in a news release:

Viruses are cut-rate brigands: They produce nothing on their own, but rather hijack the machinery of our cells. Hepatitis C, dengue, Ebola and other viruses hop onto molecular 'buses' that whisk cargo between cell compartments. These buses shuttle the viruses around inside of cells. The buses’ routes and fares are regulated by numerous cellular enzymes.

Plenty of different kinds of viruses have to climb aboard these molecular public-transport vehicles in order to enter cells, assemble themselves inside, and break out into the circulation so they can infect other cells. So, in principle, boosting those buses' fares high enough, even temporarily, could deprive a wide variety of viruses of their modus operandi.

Accessing publicly available databases, Einav's team discovered that two drugs -- erlotinib (Tarceva) and sunitinib (Sutent), both of which were approved by the Food and Drug Administration more than a decade ago for various cancer indications --  impede the action of a couple of enzymes our own cells produce that, among other things, lower the fares charged by cells' molecular buses by tweaking them so they bind more strongly to their cargo.

Might simultaneously giving erlotinib and sunitinib to mice for several days -- at doses equivalent to those proven to be safe for long-term administration to people with cancer -- price intracellular bus fares beyond the viral budget?

Yes.

In experiments with laboratory mice, survival among mice infected with dengue or Ebola viruses -- which are quite different from one another but which both travel along the same bus route -- was greatly improved if those mice also received the two-drug combo, provided that treatment began before the symptoms cropped up.

Einav is intent on moving the erlotinib/sunitinib duo into clinical trials.

Previously: Study reveals human genes, non-essential to us, that dengue, Zika, hepatitis C viruses depend on, Can a single drug outsmart many kinds of viral invaders? and Found: Ebola's entry point into human cells
Photo by NIAID

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