Experimental Drug Shows Success in Targeting Key Pathway in Recurrent Ameloblastoma

At age 20, a man was diagnosed with an ameloblastoma in his right mandible. Standard treatment for this extremely rare tumor includes repeated surgical resection. There are no standard therapies or approved drugs for this rare tumor.

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Local recurrence is common with ameloblastomas, and the patient endured numerous surgical debulking and reconstructive procedures of the mandible, orbit, and calvarium over the ensuing nine years. The combination of the disease and the procedures left his face severely disfigured, resulted in vision loss in the right eye, made eating difficult, and caused constant pain.

After doctors determined that further surgery was no longer possible, the patient learned about a first-in-human phase I trial that might offer hope. Mass General Brigham Cancer Institute is a lead site in the trial, which is studying a novel direct Wnt/β-catenin inhibitor, FOG-001, from Parabilis Medicines.

A case report published in The New England Journal of Medicine describes the patient's durable response to the therapy. "To our knowledge," the authors write, "this is the first report of clinical response to Wnt/β-catenin targeting in ameloblastoma and supports exploring FOG-001 development in Wnt/β-catenin altered solid tumors."

Wnt pathway activation is common across cancers

Medical oncologist Sam Klempner, MD, principal investigator of the trial, notes that colon cancer, stomach cancer, desmoid, and other tumors commonly co-opt and activate the Wnt pathway. This, in turn, drives tumor growth and can impair immune therapies.

The trial is studying FOG-001 in various cancers that have alterations that can result in Wnt pathway activation. "We didn't know exactly what type of tumors it would work the best in," Dr. Klempner says. "But we had a hypothesis based on preclinical models and scientific literature that tumors with Wnt pathway activation, particularly β-catenin-activating mutations, would have the best chance of responding. And that seems to be borne out in the trial so far."

The patient featured in the case report had received excellent maxillofacial and dental care near his home in Michigan. However, following multiple operations, he had no remaining surgical options. In addition, a prior attempt with radiation had failed. He had already lost vision on the right side from the ameloblastoma, and persistent tumor growth was now causing compression of the brain and worsening quality of life.

The patient had educated himself about ameloblastoma, and prior testing had picked up several Wnt pathway–activating alterations in his tumor. He contacted Mass General Brigham after reading about the trial on ClinicalTrials.gov. He was informed that ameloblastoma had not yet been treated with FOG-001. Undeterred, the patient decided to enroll.

A dramatic radiographic response

FOG-001, an intravenous drug, is designed to interfere directly with a critical step in the Wnt pathway. The patient started on the drug in April 2025. MRI images taken throughout the trial demonstrated a dramatic radiographic response, with near resolution of several tumor masses, resolved compression of the brain, and midline shift.

"The bulky facial tumors basically melted away," Dr. Klempner says. "With tumor response, his pain resolved. Also, he can now more easily open his mouth, so he has an easier time eating and speaking. He is working full-time, has returned to other day-to-day activities, and reports this is the best he has felt in 10 years."

Now a year on the trial, the patient continues on therapy. He has tolerated the therapy well, other than experiencing minor fatigue and some elevated laboratory values that will need to be monitored. He previously flew to Boston weekly to receive treatment (as the trial is not available near his home) but now does so every other week for the most part.

Seeing encouraging activity in other tumor types

The study investigators have presented data demonstrating the encouraging activity of FOG-001 in other tumor types with similar mutations. Dr. Klempner is hopeful that this approach to targeting the Wnt pathway will have increasingly widespread applicability.

"The cancer world has known about this pathway for a while; it's just that this may be the first drug to directly interfere with the critical interaction of β-catenin and its targets, and to do so in a safe way," he says. "So, it may open the door to targeting other tumor types where this pathway is turned on. We hope it may be the tip of the iceberg for targeting Wnt pathway–activated tumors, potentially like a new targeted therapy."

Dr. Klempner looks forward to seeing what happens next with FOG-001. He cites great enthusiasm at Mass General Brigham for the long-term possibility of getting approval for the drug and expanding its activity by exploring combinations with other therapies.

"The progress we've made so far speaks to our team science approach at Mass General Brigham Cancer Institute," he concludes. "Make a clinical observation, take the observation back to the lab, test it more in the lab, and then hopefully bring it back to the clinic with even greater understanding. This work highlights the true end-to-end capabilities of a center like ours."

If you have a patient with a confirmed Wnt family alteration and have questions about trial enrollment, please email mghtermeerreferrals@mgh.harvard.edu or call 866-493-1612.

Learn about Mass General Brigham Cancer Institute

Call 855-776-4224 to refer a patient to Mass General Brigham Cancer Institute