Samuel Klempner, MD
When 28-year-old Jacob Sloniker first met Mass General Brigham Cancer Institute medical oncologist Samuel Klempner, MD, Jacob was coping with the aftermath of extensive facial surgeries and the prospect of losing an eye.
Eight years prior to that first meeting with Klempner, Jacob was diagnosed with ameloblastoma, a rare tumor of the jaw that originates in the enamel cells of the teeth. While classified as “non-malignant,” ameloblastoma can invade surrounding tissue, causing severe damage to the face and jaw.
Since his diagnosis, Jacob had undergone multiple surgeries to remove tumors that were affecting his jaw, his face, and his brain, to the point where surgeons were running low on options. Jacob had arrived in Boston to meet with Klempner shortly after a tumor had ruptured his right eye.
From his surgeon in Michigan, where he lives, Jacob had heard about Klempner and a clinical trial Klempner was overseeing to test a new therapy for solid tumors with certain mutations. Jacob’s surgeon believed that his tumor biology might be a match for the therapeutic being tested.
“At that point, I’d been through so many surgeries, I was at my wit’s end,” Jacob says. “I was willing to try anything that they thought would work.”
Jacob’s case was a longshot. When he first learned about the trial, there were no effective therapies or cases reporting a clinical response for the type of ameloblastoma he had—one that harbors mutations in what’s known as the Wnt/β-catenin pathway.
However, the trial, which is sponsored by Parabilis Medicines, was testing a drug designed to hit this pathway in a new way. When Klempner told Jacob about the details of the trial, Jacob didn’t hesitate to sign up, even though they would be venturing into uncharted waters together.
“I'm an accountant by trade, so looking at the cost benefit of what could potentially go wrong versus what it could potentially do for me, it was a pretty easy decision for me personally.”
Hitting the Sweet Spot
To understand the novelty of the trial, and why it had been so difficult to find a good treatment for patients like Jacob, it helps to understand what Wnt does in healthy cells.
First identified more than 40 years ago, Wnt is part of a complex communications system that cells use to coordinate embryonic development, cell growth, and more.
Mutations to Wnt or other members of its network—known as the Wnt/β-catenin signaling pathway—can lead to the unchecked growth of cancer cells.
“In some cancer cells, we know this is a pathway where if you shut it down, the cells die,” Klempner explains. “Treatments targeting the pathway work great in the lab. But targeting it in people has been extremely difficult because several normal tissues utilize Wnt signaling as well.”
But researchers thought that maybe the issue wasn’t the pathway itself, but where and how it’s being targeted. Hitting a different key node in the pathway might offer some more selectivity for tumor cells.
While Jacob’s tumor is extremely rare, mutations to Wnt/β-catenin aren’t. It’s a frequently activated pathway, especially in colorectal cancer where it’s thought to be involved in nearly 70% of cases. In 2024, Parabilis launched the first-in-human clinical trial of a novel Wnt/β-catenin inhibitor FOG-001, now known as zolucatetide.
This experimental therapy targets the pathway in a novel location, directly blocking the interaction that allows β-catenin to turn on disease-driving genes.
The ongoing Phase 1/2 trial that Klempner is leading will help investigators determine whether this new Wnt/β inhibitor, known as zolucatetide, can hit a sweet spot of destroying cancer cells while being safe and tolerable for patients.
A Team Effort
Before Jacob could begin the trial, Klempner referred him to Mass Eye and Ear to have his right eye removed—it had ruptured due to pressure from his tumors. The operation was successful, and a few weeks after recovering from the surgery, Jacob enrolled in the study. He began receiving intravenous infusions of the experimental treatment each month.
“The staff made the whole process really easy,” says Jacob. “Especially when I arrived originally and wasn’t in good shape. They helped to set up all the other appointments for me with physicians at Mass General Brigham who weren’t even part of the trial. Whenever I had questions, they were so helpful.”
Researchers assessed Jacob frequently with imaging and blood work, and recently, in The New England Journal of Medicine in June, they described Jacob’s impressive response, now ongoing over a year since starting on trial.
“To our knowledge, this is the first report of clinical response to Wnt/β-catenin targeting in ameloblastoma,” Klempner and his colleagues wrote.
A Path Forward
For Jacob, the clinical trial has given him a path forward towards a more normal life.
“I go into the office a lot more now and have a good schedule—it’s nice to get to see my co-workers,” he says. “I went to a Pistons game recently. After going through a lot in my early 20s, I’m trying to get back to a kind of normal.”
While Klempner is thrilled to see Jacob’s progress, he cautions that this is still a phase 1 trial and the start of a journey—no one yet knows where the data will go.
“This is the story of only one patient, so we can’t claim victory, but this could be the beginning of hitting a target we weren’t sure was targetable, not so different from all the excitement around KRAS in pancreatic cancer. We hope this example is part of how the next wave starts.”
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