Novel Claudin-18.2 Radiopharmaceutical Pair Shows Curative Potential in Gastric and Pancreatic Tumors
A newly developed radiopharmaceutical theranostic pair has demonstrated the ability to precisely detect and effectively treat gastric and pancreatic tumors, completely eradicating tumors in some preclinical models. Targeting the biomarker claudin-18.2, this approach could represent a major step toward durable disease control—and possibly a cure—in some of the most challenging-to-treat solid tumors. The findings were published in the January issue of The Journal of Nuclear Medicine.
Advanced upper gastrointestinal cancers, including esophageal, gastric, and pancreatic malignancies, account for roughly one-third of cancer-related deaths worldwide. Treatment options for advanced disease remain limited, with current therapies offering only modest survival benefits, underscoring a critical unmet clinical need.
“Claudin-18.2 recently gained clinical attention following U.S. Food and Drug Administration approval of the gastric cancer therapy zolbetuximab,” said Shadi Esfahani, MD, MPH, a nuclear medicine physician at Massachusetts General Hospital. “To further explore the utility of claudin-18.2, my colleagues and I developed a first-in-class claudin-18.2–targeted PET radiopharmaceutical and a therapeutic counterpart to identify and treat gastric and pancreatic tumors.”
In the study, researchers evaluated the theranostic pair in murine models bearing gastric or pancreatic tumors. Serial PET imaging was performed using ^89Zr-DFO-zolbetuximab, with a non-targeted IgG tracer as control, followed by biodistribution analysis. Tumor-bearing mice then received a single intravenous dose of ^177Lu-DOTA-zolbetuximab (high or low dose) or various control treatments.
PET imaging showed consistently high tumor uptake of ^89Zr-DFO-zolbetuximab at all time points, significantly exceeding uptake of the control tracer. Therapeutically, high-dose ^177Lu-DOTA-zolbetuximab led to marked tumor growth reduction in both gastric and pancreatic models, with complete regression of most pancreatic tumors. Importantly, no radiation-induced toxicities were observed.
“Claudin-18.2–based theranostics could meaningfully change patient care,” Esfahani noted. “Targeted PET imaging allows noninvasive identification of patients whose tumors express this biomarker, while radiopharmaceutical therapy can deliver focused radiation directly to tumor cells, offering the possibility of improved survival.”
She added that the work highlights how advances in biomarker discovery, molecular imaging, and patient selection are moving nuclear medicine closer to therapies with true curative potential rather than incremental benefit.