How protein-slayer drugs (PROTACs) could beat some of the cruelest cancers

A little boy named Evan Lindberg was diagnosed at age three with neuroblastoma – a childhood cancer of nerve cells. Despite years of intensive treatment (chemotherapy, radiation, immunotherapy, multiple surgeries – you name it), the cancer kept coming back. For four years, Evan never really got a break from fighting or recovering. Heartbreakingly, he passed away at seven years old. His oncologist, Dr. Yael Mossé, has spent over two decades trying to find better options for neuroblastoma. “We have made very little progress in developing more targeted therapies", she admits. Unfortunately, she’s right – childhood solid tumors like Evan’s remain extremely hard to treat. They’re biologically different from adult cancers and need kid-specific drugs, yet out of more than 180 cancer drugs approved since 2000, fewer than a dozen were developed for children. In short, some of the most cruel cancers – aggressive pediatric tumors and late-stage adult cancers – have long defied our best medicines. Families like Evan’s are left desperate for new approaches when standard treatments don’t work.

Why some cancers evade current drugs

Why do traditional cancer drugs fail in cases like these? Often, it comes down to the cancer’s power source – certain proteins that cancer cells rely on. Many modern cancer drugs are designed to block a protein’s activity. Think of slipping a key into a lock to gum it up, stopping the machinery. But some cancer-driving proteins don’t have a nice “lock” for a drug to jam. Evan’s tumor, for instance, was driven by an overactive gene called MYCN, which produces a transcription-factor protein that acted like a stuck accelerator pedal for tumor growth. There’s no easy pocket on MYCN’s protein for a drug to bind to, making it notoriously “undruggable”. It’s a common problem – of roughly 3,000 proteins known to cause disease, current drugs target fewer than 700, and the rest have been essentially off-limits. Even when we do have drugs for a cancer protein, tumors can be crafty. They often mutate or find backup pathways to keep growing, rendering drugs ineffective over time (For example, advanced prostate tumors eventually outsmart standard hormone-blocking pills, and certain leukemias become resistant to their targeted drugs.) In some cases, underlying factors like chronic inflammation quietly fuel the cancer’s fire, meaning just blocking one protein isn’t enough. All this explains why doctors have been eager to find a new strategy to truly shut down these stubborn cancers.

A new way to disarm rogue proteins

Enter the PROTAC – a mouthful shorthand for “proteolysis-targeting chimera". In plain terms, a PROTAC is a small designer molecule that doesn’t just block a bad protein; it destroys it. How? It cleverly hijacks the cell’s own garbage disposal system. Imagine you have a troublemaker protein that the cell isn’t dealing with. A PROTAC works like a matchmaker between that bad protein and the cell’s destruction machinery. It binds to the disease protein on one end and to an enzyme called a ubiquitin ligase on the other end – that enzyme’s job is to tag proteins with “dispose of me” labels. Once the PROTAC brings the enzyme and the target together (scientists call it giving the target a “kiss of death”), the target protein gets tagged and sent to the proteasome, the cell’s shredder. The harmful protein is chopped up and eliminated completely. Not only that, the PROTAC molecule then lets go and can go on to trigger the destruction of another copy of the bad protein, again and again. In this way, even a small dose can wipe out a lot of the dangerous protein. One researcher quipped that PROTACs “take no prisoners” – by removing the protein entirely, they eliminate all of its contributions to disease. This approach expands the reach of drug therapy: a PROTAC doesn’t need to find a hard-to-fit lock on the protein, it just needs any little grip to latch on, and the cell’s own system does the rest. It’s a fundamentally different, more aggressive way to disarm cancer’s molecular villains.

Figure 1: Protein eliminated. Drugs called PROTACs (short for proteolysis-targeting chimeras) can destroy a disease-causing protein by tethering it to an enzyme (a ubiquitin ligase) that tags the protein with ubiquitin markers (green) for destruction by proteasomes (the cell’s recycling units). The PROTAC (blue) links the target protein (red) to the ligase (gray), giving the target a “kiss of death.” The tagged protein gets shredded, and the PROTAC is released to hunt down another target. In essence, a PROTAC doesn’t just block the bad protein – it completely removes it from the scene.

Using the cell’s internal clean-up crew to fight cancer might sound like science fiction, but the concept has rapidly moved from labs to the clinic. (Biology is full of surprises – for instance, something as odd as a tick bite can trigger a severe red-meat allergy later in life, so harnessing a built-in protein disposal system is not as far-fetched as it seems!). In fact, what started as a quirky laboratory idea about two decades ago has blossomed into a whole new class of drug candidates. Early skeptics thought these bulky molecules would never work as medicines, but by 2015 several teams showed potent PROTACs that could wipe out target proteins in cells and even in mice. After that, the floodgates opened – labs around the world, from small biotechs to big pharma, jumped into the protein-degrader arena. Scientists sometimes compare it to the advent of a new wave of targeted drugs. The excitement is understandable: PROTACs offer hope for attacking targets long deemed “undruggable” and for knocking out disease drivers in a more thorough way than traditional drugs.

Early signs of success

All this promise would mean little if PROTACs didn’t show real results in patients. Fortunately, they are starting to. Over 30 different PROTAC drug candidates have entered human clinical trials since 2019, mostly for cancers but also for diseases like Parkinson’s and chronic inflammatory conditions. No PROTAC has been approved by the FDA yet, but a few are now in the final stretch of testing. The first PROTAC to reach a phase III trial is vepdegestrant, a drug that targets the estrogen receptor which many breast cancers depend on. In a recent report, vepdegestrant helped patients whose tumors had a certain mutation (one that usually makes cancer harder to treat) stay progression-free longer than those on the standard therapy This was a key subgroup analysis indicating the PROTAC was especially effective for those tough cases, even though the overall trial population saw similar outcomes either way. The fact that it performed better in mutation-resistant tumors is a big positive sign. Arvinas, the company co-developing vepdegestrant with Pfizer, announced plans to discuss these data with regulators soon. Meanwhile, two other PROTACs have also advanced to phase III trials: one targets the androgen receptor, the engine of most metastatic prostate cancers, and the other targets BTK, a protein essential for certain leukemias (like chronic lymphocytic leukemia). We already have drugs against AR and BTK, but in advanced cancers the disease inevitably becomes resistant to those standard drugs. The hope is that by degrading these proteins entirely, the PROTACs can overcome resistance and shrink tumors that have stopped responding to anything else. In early-phase studies, the PROTAC for prostate cancer has shown some tumor responses even in patients who had no options left, giving a glimmer of hope in a dire setting. Larger trials will tell if it truly improves survival. Still, seeing multiple “protein-slayer” drugs reach late-stage trials within just a few years is remarkable. It tells us this approach isn’t just theoretical – it’s already helping some patients, and could soon become an approved treatment for others.

Slaying the toughest childhood cancers

Perhaps the most ambitious push for PROTACs is in the area that Dr. Mossé cares about most: childhood solid tumors like neuroblastoma. These cancers – including brain tumors, bone cancers (like Ewing sarcoma and osteosarcoma), and liver tumors – are among the leading causes of cancer deaths in children. Many are driven by genetic quirks such as fusion proteins (when two genes crash together to create a novel cancer-causing protein) or overactive developmental genes like MYCN. Traditional drug development has largely overlooked these targets, but now researchers are going after them with protein degraders. Mossé herself co-leads a global team called KOODAC (Knocking Out Oncogenic Drivers to Cure Childhood Cancers) that is developing PROTACs against five formerly untouchable cancer drivers in kids. Among them is MYCN (the very factor that made Evan’s neuroblastoma so aggressive) and three different fusion proteins that cause terrible cancers such as Ewing sarcoma, rhabdomyosarcoma (a soft-tissue cancer), and a rare childhood liver cancer. It’s a bold, riskier strategy – instead of repurposing existing drugs, they’re targeting proteins that have never been drugged before. If it works, it could be revolutionary. Mossé expects their first PROTAC candidates to reach clinical trial in the next couple of years. Uniting scientists across the US, UK, Europe and even including patient advocates on five continents, the KOODAC project is also prioritizing practicality: they aim to develop treatments that are not only effective, but also easy to give (ideally pills, not IV infusions) and affordable in all parts of the world. This matters because in low- and middle-income countries, high-cost or hospital-intensive therapies often aren’t accessible – many families have to abandon treatment due to cost or distance. The organizers want PROTAC cures that any child could receive, no matter where they live or how much money they have. It’s an inspiring goal born out of tragedy – Evan’s parents, Gavin and Wendy, joined KOODAC as advocates after losing their son, determined to help other families avoid the same fate.

Will PROTACs actually cure these childhood killers? It’s far too soon to say, but scientists are cautiously optimistic. Charles Mullighan, a pediatric cancer researcher at St. Jude Children’s Research Hospital, notes that targeted degraders show real potential in lab tests for tough leukemias and brain tumors. However, he and others also warn that cancer is wily – even if you knock out one driver protein, the cancer might adapt or find a new fuel source. In the future, PROTAC drugs might need to be combined with other treatments (like chemotherapy, immunotherapy or gene therapies) for a one-two punch. “Cancers are clever and can find ways around it,” Mullighan says, reminding everyone to temper enthusiasm with realism. Still, the ability to drug the “undruggable” is a game-changer. It opens doors that have been closed for decades. For doctors like Mossé – and parents like the Lindbergs – just having something to try against these lethal childhood cancers is a huge leap forward. Even incremental improvements will save young lives.

Turning hope into help

The story of PROTACs is ultimately a story of hope emerging from frustration. It shows how innovative science can offer a lifeline where there was none. Of course, developing new cancer drugs takes time, and patients facing rare or aggressive diseases need support in the here and now. That’s where SlothMD strives to make a difference. We know that navigating a complex condition can be overwhelming for patients and their families, so we aim to lighten that burden. SlothMD helps families organize medical records and care histories at home, and even uses AI to assist with finding the right doctors or managing insurance and appointments. In other words, while scientists work on breakthrough treatments like PROTACs to defeat disease, we help everyday people manage the journey. It’s a humble but important mission: ensuring no one has to face a rare or difficult health battle alone. With cutting-edge therapies on the horizon and compassionate support systems in place, we are moving toward a future where even the cruelest cancers can be met with knowledge, hope, and eventually, a cure.