Escaping the Executioner Protein

What’s the difference between a heart attack and heart failure?

In a heart attack, blood flow to the heart muscle is suddenly cut off. The cause is usually a disease process called atherosclerosis, in which fat, cholesterol and other substances accumulate in the coronary arteries that provide oxygenated blood to the heart. When this “plaque” ruptures, a blood clot may form around it, clogging the arteries and depriving heart muscle of oxygen. Symptom

"When it comes to life-and-death decisions in a cell, a protein called BAX has the last word," says Evripidis Gavathiotis, Ph.D., an assistant professor of biochemistry and of medicine. BAX does its deadly work following heart attacks, by orchestrating the killing of heart muscle.

"This 'executioner protein' attaches to a cell’s mitochondria, the energy 'power plants’ contained in cells," explains Dr. Gavathiotis. "BAX then creates holes in the membranes of mitochondria, draining cells of their energy supply." The cells never have a chance to heal. Heart failure may follow—the result of the heart-muscle damage caused by BAX.

This article originally appeared in the Summer/Fall issue of the Wilf Family Cardiovascular Research Institute newsletter.But what if the death sentence could be commuted?

Richard N. Kitsis, M.D., director of the Wilf Family Cardiovascular Research Institute, met Dr. Gavathiotis at a professional meeting in 2010, and their conversation soon revealed a shared passion for cell-death pathways in general and BAX in particular.

Stay of Execution

Dr. Gavathiotis had succeeded where many had failed: he had identified key spots on BAX where the protein can be turned off. "We found three different spots on the structure of the BAX protein that we can target to inactivate BAX,"says Dr. Gavathiotis. "You can think of them as BAX’s Achilles’ heels."

Having made the move from the Dana Farber Cancer Institute/Harvard Medical School to Einstein in 2011, Dr. Gavathiotis is now looking for drugs that will target BAX and turn it off—thereby preventing the heart failure that all too often follows heart attacks. Like many Einstein researchers, he uses a computer as well as a microscope in his search.

"On the computer, we can screen thousands of molecules that potentially will bind to our target," he says. Once the computer’s mathematical algorithms and functions reveal molecules with BAX-binding in the laboratory that the molecules do indeed bind to BAX. "If so, we’ll test those molecules in cells and in rodents to see if they can prevent death of heart-muscle cells and, more important, protect the heart’s function," he says. The most promising of those molecules might become drugs that could save the lives of some of the more than 400,000 Americans who die of heart failure each year.

Bad Guy’s Good Side

Curiously, the protein that’s such a threat following heart attacks may actually be a hero under other circumstances. "Cancer cells have found a way to prevent BAX from doing its job of inducing cell death," says Dr. Gavathiotis. "The cells survive and proliferate, driving tumor growth. Since we had discovered the places on BAX that we could target to turn it off, we then started seeking a molecule that can turn BAX on and induce cancer-cell death. We’d have to do it specifically to cancer cells while sparing the normal cells," he says.

Dr. Gavathiotis and his colleagues recently made a significant advance in their search for a BAX turn-on: They reported in Nature Chemical Biology that a small molecule called BAM7 can activate BAX. BAM7 is currently undergoing extensive tests in blood and solid-tumor cancers and will, the researchers hope, become the first of a new class of targeted medicines that can kill cancer cells.