Northwestern University researchers have designed polymer “trash collectors” that grab cancer’s most stubborn proteins and drag them to the cell’s waste bin. The approach halted tumor growth in mice and could open the door to new treatments for cancers long considered undruggable.
For decades, some of cancer’s most dangerous proteins have been labeled too tough to target with drugs. Now, Northwestern University scientists have found a way to stop fighting those proteins head-on and instead send them straight to the cellular trash.
In a new study, researchers engineered protein-like polymers, or PLPs, that latch onto cancer-driving proteins and escort them to the cell’s waste-disposal machinery. Once there, the proteins are broken down and cleared away, triggering cancer cell death and slowing tumor growth in early tests.
The work, published in Nature Communications, takes aim at two of the most notorious cancer culprits: MYC and KRAS. These proteins help drive uncontrolled growth in many tumor types and have long frustrated drug developers.
“MYC and KRAS drive a huge fraction of human cancers — often aggressive ones — and effective drugs for them are extremely limited,” study leader Nathan Gianneschi, a professor of chemistry, materials science and engineering, biomedical engineering and pharmacology at Northwestern, said in a news release.
Most modern cancer drugs try to block a protein’s activity by fitting into a precise pocket on its surface, like a key in a lock. But many cancer-driving proteins, including MYC and KRAS, are floppy or disordered and lack a clear pocket. That makes it extremely difficult for traditional small-molecule drugs or antibodies to get a good enough “handle,” to bind and shut them down. These targets are often described as “undruggable.”
The Northwestern team took a different tack. Instead of trying to jam the lock, they built a system to throw away the entire lock.
Their PLPs, and a specific class of them called HYDRACs (HYbrid DegRAding Copolymers), are long, flexible chains decorated with multiple functional parts. Some parts are short protein fragments, or peptides, that recognize and bind to a target protein such as MYC or KRAS. Other parts act as signals that call over the cell’s natural protein-degradation machinery.
This strategy taps into a quality-control system that every cell already uses to find and destroy old, damaged or unneeded proteins. HYDRACs essentially hijack that system and redirect it toward disease-causing proteins.
Gianneschi described the design in simple terms.
“Each PLP essentially has two hands,” he said. “One hand grabs the protein, and the other hand grabs the cell’s ‘dust bin.’ It’s literally like picking up a piece of trash off the ground, grabbing the waste basket and putting them near each other.”
By bringing the target protein and the degradation machinery together, the polymers ensure that the protein is tagged and dismantled. Because the entire protein is removed, the approach does not depend on blocking a single site or mutation.
In cell culture experiments, HYDRACs built to recognize MYC selectively degraded that protein in cancer cells. As MYC levels dropped, MYC-driven genes shut down and the cancer cells died. In mouse models with MYC-driven tumors, the MYC-targeted HYDRACs accumulated in tumors, reduced cancer cell proliferation and halted tumor growth, without significant side effects reported in the study.
To show that the platform is flexible, the team then reprogrammed the polymers to target KRAS, another high-profile cancer driver found in about a quarter of human cancers, including many pancreatic and colorectal tumors. While a few small-molecule drugs have recently been approved for specific KRAS mutations, they only work for narrow subsets of patients and often stop working as tumors evolve.
“In the last few years, researchers have developed small molecule drugs that target specific KRAS mutations,” Gianneschi added. “In many cases, patients became resistant to the drugs as the cancer mutates to resist treatment. That’s because cancer cells work incredibly hard to evade therapies, especially when they’re hitting a protein target at the core of the tumor’s survival.”
In lab tests, the KRAS-targeting HYDRACs successfully degraded KRAS proteins in cancer cells, including versions carrying different mutations. Because the polymers do not rely on a single mutation site, they may be less vulnerable to resistance.
“That’s the advantage of the multivalent, polymer-based degrader strategy we have developed,” added Gianneschi. “It doesn’t matter if a protein mutates, it’s still going into the bin. KRAS can be actively changing, kicking and screaming all the way to the trash can, but all we need to do is destroy the whole protein. This is a potentially powerful way to foil the cell which cannot easily mutate away from your drug.”
The concept builds on a growing field known as targeted protein degradation, in which drugs do not simply block proteins but mark them for destruction. Most degraders developed so far are small molecules, which still struggle with disordered, pocket-free proteins like MYC and KRAS. By using larger, polymer-based structures with multiple binding sites, the Northwestern team hopes to overcome those limits.
Giannesch emphasized that the chemistry behind the platform is deliberately streamlined.
“We developed a one-step polymer chemistry solution,” he said. “The protein mimetic polymers engage disordered proteins and bring them together with the cellular machinery that degrades it. That had never been done before, and it proved effective against some of the most challenging targets in cancer biology.”
While the current study focused on cancer, the researchers see broader potential. Many neurodegenerative, inflammatory and metabolic diseases are driven by harmful proteins that build up or misbehave in cells. In principle, HYDRACs could be redesigned to recognize those proteins and send them to the trash as well.
“By demonstrating this platform with two completely different undruggable proteins, we think it might work to open up other targets,” Gianneschi added. “It’s a new way to think about targeted treatments. It’s not just about finding the perfect small molecule. It’s about designing systems that can work with the cell to eliminate many different harmful proteins altogether.”
Grove Biopharma, a company spun off from Northwestern, has licensed the intellectual property for the technology from the university and is advancing it as part of its Bionic Biologics platform, with the goal of moving toward clinical development. Gianneschi and the university hold financial interests in the company.
For now, the findings are still in the experimental stage, tested in cells and animal models rather than in people. Much more work will be needed to understand how safe and effective these polymers are in the human body, how best to deliver them and which patients might benefit most.
But by turning cancer’s toughest proteins into cellular garbage, the approach offers a fresh angle on some of oncology’s hardest problems — and a glimpse of a future in which even “undruggable” targets may no longer be out of reach.
Source: Northwestern University