For the past two decades the drug thalidomide—made infamous in the 1950s and 1960s for causing severe birth defects—has had a second act as a cancer therapy. It has proved particularly effective against the blood cancer multiple myeloma, halting the malignancy at its roots in the bone marrow. Yet despite the medication’s life-extending results, researchers have had trouble explaining exactly why it works.
Now after years of study scientists have started unraveling key details about thalidomide’s machinations in the body. Their findings suggest the drug, and others that function similarly, may hold untapped potential for beating additional types of cancer—as well as disorders like Alzheimer’s—because they may be able to rid the body of proteins that fuel disease.
The drugs’ versatility appears to hinge on their ability to hijack a cellular trash-disposal mechanism. Researchers working with mice discovered in 2010 thalidomide attaches a key tumor-causing protein to the regulatory protein cereblon (CRBN). This change signals to the trash-disposal system that this molecular structure must be eliminated—somewhat like putting a garbage can out on the curb. Tragically, thalidomide can also recruit and tag for destruction a protein required for fetal limb development, leading to birth defects.
Pharmaceutical companies are now trying to harness this tagging-for-disposal approach with many other proteins that can cause disease. Their work has given rise to a new area of drug research called “protein degradation therapy”—a term of art referring to treatments that zero in on and eliminate proteins known to wreak havoc in the body. Researchers in this field have started with cancer, where the molecular targets are relatively clear. Later, researchers also hope to use these same approaches with diseases like Alzheimer’s and Parkinson’s.
Of course, scientists have been trying for decades to get rid of damaging proteins. A major class of medications in current medicine, called “small molecule” drugs, is based on this idea. Medicinal chemists design these molecules to fit into tiny, pocket-shaped spaces in a protein in an attempt to alter the protein’s shape so it is no longer capable of binding with any cellular receptors where it can do damage.
But many proteins either lack such convenient pockets or cannot be stymied by this kind of jamming. This is where the protein degradation approach comes in handy: Instead of needing to effectively gum up a pocket, scientists have to figure out how to metaphorically flag down the trash truck.
Many major pharmaceutical companies are currently studying the concept, according to industry experts. “That’s the promise—that you’ll be able to target a range of things,” says Aseem Ansari, a professor of biochemistry at the University of Wisconsin–Madison who is involved in this area of research. Despite thalidomide’s success, protein degradation so far remains largely untested in humans—and it will probably be several years before early trials in patients can advance enough to prove the approach will work beyond multiple myeloma.
Biotechnology start-ups are jumping in, notes Ian Taylor, senior vice president, biology, for Arvinas—a biotech firm founded by Yale University professor Craig Crews, who is considered the father of protein degradation therapy. Another start-up called Cedilla Therapeutics recently announced it had raised $56 million in initial funding. Cedilla’s Web site mentions a cancer focus, but the company has not yet revealed any specific targets for its potential protein degradation therapy. There are at least five to 10 other small companies moving into this field, Taylor says.
“It seems like a new company springs up every couple of weeks,” says Taylor, whose own enterprise hopes to be the first to test protein degradation on human subjects. Arvinas is launching a trial later this year in patients with prostate cancer, aiming to degrade the receptor for androgens; that protein, which binds male hormones, has long been a target for prostate cancer therapy. Animal research suggests this protein degradation approach would eliminate cells’ androgen receptors altogether, thus limiting the amount of hormones like testosterone the body could produce. Degradation, Taylor says, removes more of these receptors than simply blocking them (the current treatment approach). And this degradation will likely make it harder for the cancer to develop resistance to this therapy—although patient trials are needed to show whether this is true.
In one of the key papers in the protein degradation field—a 2015 study published in Science that convinced drug companies the approach had promise beyond multiple myeloma—a team at the Dana–Farber Cancer Institute injected mice with a thalidomide-like drug. This degraded a protein called BRD4—essential for leukemia growth in both mice and people. “To our delight and amazement the targets of these molecules were degraded by the cell in as early as 15 minutes, and by an hour they were almost completely gone,” says Jay Bradner, an oncologist and the study’s senior author.
BRD4 was the only protein destroyed, suggesting a similar-acting drug would be safe, adds Bradner, now president of Novartis Institutes for BioMedical Research, the research arm of one of the world’s largest pharmaceutical companies. “We were really leveraging this beautiful evolutionarily selective biological process,” he says.
Milka Kostic, program director of chemical biology at Dana–Farber, likens the specificity of protein degradation to unlocking a cell phone by tracing a unique pattern with one’s finger. Typical small-molecule drugs—such as aspirin—instead unlock a door with a key that might have many copies, Kostic notes.
Part of the promise of protein degradation, Yale’s Crews says, is that it is based on medicinal chemistry—the same work pharmaceutical companies have been doing for decades—rather than on the manipulation of RNA or genes, like other new therapeutic approaches. Drug companies are more familiar and more comfortable with medicinal chemistry than newer approaches, says Crews, who has been working in the field for more than 17 years.
This flurry of activity in the protein degradation field is also poised to enhance researchers’ basic understanding of the role certain proteins play in the body. Kostic notes scientists are already using the approach to degrade the human body’s 20,000 proteins one at a time in the lab, to see what they do and how the body might function without them. Similar work is going on with CRISPR gene editing, she says—but protein degradation works faster and thus allows scientists to ask different questions, such as what happens if protein levels fall rapidly. “I view CRISPR and the degraders as two very complementary ways in which you can start to ask what happens if we remove one thing out of the entire proteome,” she says, referring to the formal term describing full catalogue of proteins in the human body.
Development of protein degradation drugs is quickly outpacing researchers’ understanding of how these potential therapies work, Kostic says. That may be okay in the short term, she adds. After all, people used willow bark (an aspirin precursor) for centuries before they understood how it functioned, and thalidomide was used on many patients as a cancer treatment before scientists understood its mode of action.
But to make more advances, Kostic says, at some point such mysteries must be solved through fundamental research. “Basic science is in a little bit of a catching-up mode,” she says, “because a lot of development has been driven by the real interest in making clinical impact.”