How protein-slayer drugs could beat some of the cruellest cancers

Momentum is building for PROTAC treatments that eliminate disease-causing proteins, including those responsible for difficult-to-treat childhood cancers

At three years old, Evan Lindberg was diagnosed with neuroblastoma, a childhood cancer that develops in nerve tissue outside the brain. By that time, tumours had spread through his small body. Chemotherapy, radiation, immunotherapy and multiple surgeries followed. “For four years, my son never had a day off,” says Evan’s father, Gavin. “He was either in treatment or recovery. And frequently recovery was worse than the treatment.” Evan died in 2010 at the age of seven.

One of Evan’s doctors, paediatric oncologist Yael Mossé at the Children’s Hospital of Philadelphia, Pennsylvania, has long sought improved treatment options. She has worked on neuroblastoma for more than two decades, yet despite small advances, “we really have made very little progress in developing more rational or targeted therapies”, she says. That’s true in general for childhood solid tumours. Although such tumours are less common than blood cancers in children, they account for more than half of cancer-associated deaths in kids aged 0–14 years¹ in the United States. These childhood cancers differ from adult ones in their biology, and thus require distinct treatments. Yet out of more than 180 cancer drugs that have received approval from the US Food and Drug Administration (FDA) since 2000, fewer than a dozen have been developed specifically for children.

Mossé is now placing her hopes on laboratory-made molecules that hijack the cell’s protein-disposal machinery. Typical drugs gum up the business end of a protein to inhibit its activity. PROTACs, short for proteolysis-targeting chimeras, eliminate the protein altogether. They do this by tethering disease-associated proteins in human cells to an enzyme that tags the protein for destruction.

Enabling these fateful encounters — which biochemist Alessio Ciulli at the University of Dundee, UK, calls a protein “kiss of death” — expands the list of possible drug targets. Of the roughly 3,000 proteins known to cause cancer and other diseases, drugs approved by the FDA, for example, target fewer than 700. Most of the rest are considered ‘undruggable’, because there’s no suitable pocket in which a drug can attach and block the protein’s activity. But a PROTAC merely has to grab on; the cell’s existing machinery does the rest.

At least 30 PROTACs have entered clinical trials since 2019, when testing in humans began, mainly for cancer, but also for Parkinson’s disease, inflammatory disorders and pain. The three most advanced, for breast cancer, prostate cancer and leukaemia, are in phase III trials, the last step before market approval. Most degrade proteins that are targeted by already approved drugs.

Evan Lindberg, pictured on the left with his father Gavin, died of cancer at age seven. Gavin is now a patient advocate, working with paediatric oncologist Yael Mossé (right) and others to develop treatments for childhood cancers.Credits: Wendy Lindberg, Children’s Hospital of Philadelphia

Mossé and her colleagues are doing something different — and riskier — by going after cancer proteins that have never been drugged before. She co-leads a team that is developing PROTACs against undruggable proteins responsible for neuroblastoma and other childhood cancers, including those of the brain, liver and bone. All of the cancers form solid tumours. Mossé expects the team’s first PROTACs to enter clinical trials in the next couple of years.

Other researchers are similarly aiming to degrade proteins that have long been considered untouchable, in cancer and beyond. “Showing that you can target something brand new with this technology will be a pivotal moment for the field,” says chemist Nathanael Gray at Stanford University in California, co-founder of C4 Therapeutics, a protein-degradation drug company in Watertown, Massachusetts.

More than a lab trick

The first working PROTAC was demonstrated in 2001, when Craig Crews, a chemical biologist at Yale University in New Haven, Connecticut, biochemist Raymond Deshaies, at the California Institute of Technology in Pasadena, and their colleagues constructed one that degraded its target protein in cell fluid from frog eggs². At the time, most scientists viewed PROTACs as a lab trick. When Ciulli started working with them in 2009, colleagues “rolled their eyes”, he recalls. “They said, ‘PROTACs? They’ll never be drugs.’”

One early hurdle was making PROTACs small enough to penetrate cells. Another was designing them to grab onto the most abundant and efficient of the enzymes known as ubiquitin ligases. These enzymes, of which there are about 600 kinds, tag proteins for destruction by attaching chains of much smaller proteins called ubiquitins (see ‘Protein eliminated’). After a large effort, three papers in 2015 revealed potent PROTACs that almost completely eliminated target proteins in cells and mice³^–⁵. “After those papers, there was no doubt that we could degrade proteins,” says Ciulli. “Now the whole world of targets could open up.” A co-author on one of the papers, Ciulli later helped to found Amphista Therapeutics, a protein-degradation company in Cambridge, UK.

The papers highlighted a key advantage of PROTACs. Whereas conventional drugs must take up residence on a disease-causing protein, PROTACs engage with their target briefly, send it along for destruction and move on to the next target. This catch-and-release feature means that very small doses can last for a long time. Another advantage is that PROTACs take no prisoners. Some proteins contribute to a disease in more ways than one, but by wiping out the protein entirely, a PROTAC eliminates all possible contributions.

The 2015 papers established PROTACs as a next wave of drugs. “I’ve never seen a technology that’s been more widely adopted, as quickly,” says Gray. “It’s not just little risky biotechs. All the pharma companies have advanced degrader programmes.”

This all happened too late for Evan Lindberg. In 2010, his father entered him into one of Mossé’s clinical trials, testing an existing drug against a protein often corrupted in neuroblastoma. Evan’s cancer did not respond. The tumour also contained extra copies of the gene for a protein that is a notorious driver of childhood cancers, the transcription factor MYCN. MYCN turns genes on to make cells replicate during childhood development. Too much of it can transform otherwise curable cancers into aggressive killers through uncontrolled growth. But transcription factors such as MYCN are considered undruggable.

At a meeting about MYCN in 2019, Mossé realized that PROTACs could be a solution. One of the founders of the PROTAC company Nurix Therapeutics in San Francisco, California, attended the meeting, and “really motivated us to think about targeted protein degradation, and to go after MYCN, to try to really do something big”, Mossé says. Armed with a private foundation grant, she began working with Nurix. The work expanded in 2024, when a team Mossé assembled along with biochemist Martin Eilers at the University of Würzburg in Germany won a large grant from Cancer Grand Challenges, a global non-profit initiative looking to tackle childhood solid tumours.

The team, called KOODAC, for Knocking Out Oncogenic Drivers and Curing Childhood Cancers, also includes scientists in the United Kingdom, Austria and France and patient advocates on five continents. Among them are Gavin Lindberg and his wife Wendy who, after Evan died, established a charitable foundation that for the past decade has funded a research position in Mossé’s lab. The team is going after MYCN and four other protein targets. The goal is to find drugs that not only work, but are also more convenient than hospital infusions and cheap enough for purchase in low- and middle-income countries, where families often have to forgo or abandon treatment because of the cost.

Slaying the childhood killers

Three of the proteins the KOODAC team is targeting result from a type of genetic error that is often present in cancer. The crossing, breaking and mending of chromosomes can give rise to a new hybrid gene — a gene fusion — that has sequences from both original genes. The resulting fusion proteins are the direct cause of many leukaemias, lymphomas and childhood solid tumours. Two of these fusion proteins drive Ewing sarcoma and rhabdomyosarcoma, devastating childhood bone and soft-tissue cancers. The third causes a rare liver cancer.

As tumour cells evolve, fusion proteins persist, making them attractive targets, says Charles Mullighan, a haematologist at St. Jude Children’s Research Hospital in Memphis, Tennessee. Mullighan and his colleagues make and test PROTACs and similar protein degraders for childhood blood cancers and brain tumours. As to whether protein degraders can cure these cancers, “there’s the potential”, says Mullighan. But he adds that one drug might not be enough. “Cancers are wily, and they can find ways around it.”

In addition to KOODAC, two other Cancer Grand Challenges teams are tackling childhood solid tumours. One team brings together researchers from nine institutions across Europe and the United States to work on protein degraders and cell therapies. The other, which includes investigators at eight institutions in the United States, the United Kingdom and France, is focused exclusively on cell therapies. Such broad academic collaborations are essential to making progress on childhood cancers, the researchers say. “For paediatric-only cancers, the market is so small it doesn’t fit the commercialization plan of a traditional pharma company,” says Catherine Bollard, co-leader of the cell-therapy team and a paediatric haematologist at Children’s National Hospital in Washington DC.

The PROTACtable universe

No PROTACs have been approved yet. The first to enter phase III trials, vepdegestrant, developed by Arvinas in New Haven, Connecticut, degrades the oestrogen receptor that most breast cancers rely on for growth. In early March, Arvinas and its partner, Pfizer, reported that the degrader was better than a standard anti-oestrogen drug at enabling trial participants whose tumours had a mutation commonly associated with breast cancer to live longer without the disease worsening (although it did not do better in an analysis that included all trial participants). “We plan to share [trial] data with global regulatory authorities to potentially support regulatory filings,” Arvinas chief medical officer Noah Berkowitz wrote in an e-mail to Nature. Two other vepdegestrant phase III trials are under way.

Meanwhile, two other PROTACs have reached phase III trials. One degrades the androgen receptor that drives most metastatic prostate cancers; the other, the BTK enzyme required by chronic lymphocytic leukaemias. Drugs against these targets are already available, but advanced cancers inevitably become resistant to them.