The human body is made up of trillions of cells, all of which are pre-programmed to self-destruct when they are no longer needed. But cancer cells have figured out how to evade this process of programmed cell death, or apoptosis, allowing them to reproduce uncontrolled. Figuring out how to restore a cancer cell’s ability to die has taken nearly two decades of work by persistent researchers. “It has taken nearly 20 years of work by so many people to get to this point,” says Andrew Petros, principal research scientist at AbbVie. “Apoptosis was a potential mechanism for killing cancer cells that no one had really thought too much about. This was something completely different.”
Mapping the target landscape
In the early 1990s a group of scientists from Abbott Laboratories, now AbbVie, wanted to better understand apoptosis. They wondered if this cellular ability to self-destruct could lead to a cancer-fighting medicine. Several proteins help in the apoptotic process, some that cause cell death and some that prevent it. But they had no idea what those proteins looked like, so there was no way to harness them for drug development.
Researchers took BCL-XL, the easiest-to-access protein, and created a picture of it using two high-powered imaging systems – nuclear magnetic resonance spectroscopy and X-ray crystallography. According to Petros, who worked on the project later on, the structure “was a novel fold and generated a lot of excitement because at the time it wasn’t clear which of the BCL proteins would be a good oncology target.”
Now they could try to discover small molecules that could bind to, and inhibit, these BCL proteins on the surface of cells, including cancer cells. The objective was to reset the cell-death program within the cancer cells and induce them to commit suicide.
Just enough to keep going
Led by Steve Fesik, then head of oncology discovery at Abbott, now at the Vanderbilt University Medical Center, the process of finding the right molecule was slow and methodical. After five years, they identified a molecule that could bind to the “active” groove on the surface of the BCL-XL protein. “There were times we thought we wouldn't be able to do it, but Steve was determined not to let this fail. And each step of the way we’d get just enough good data to convince people we should keep working at it,” says Petros.
The molecule proved potent at activating cell death, but had no oral bioavailability; it couldn’t be made into a pill because the body wouldn’t be able to absorb it. It would have to be injected, but cancer patients and oncologists have historically been more receptive to pills than injections.
A eureka moment
It would take another two years of formulation work, only to find more issues emerge in the clinic. Back to drawing board, they realized that there were several other apoptotic proteins they hadn’t previously considered. “Based on extensive biological studies, we realized BCL-XL was the problem and we shifted our focus to another protein in the family,” says Petros. “But we didn’t have to start over; we had structural insight.”
Four years later, the researchers have continued to advance the science of the BCL family of proteins, including coming back to BCL-XL. In early 2015, Science Translational Medicine published a paper detailing the foundational biology work being done by AbbVie scientists on the BCL-XL protein and its role in solid tumors, giving hope that it may yet prove to be a good target.