A research team at Massachusetts General Hospital has developed a novel theranostic radiopharmaceutical approach targeting claudin-18.2, demonstrating both detection and treatment capabilities in preclinical models of gastric and pancreatic tumors.

The findings, published in the Journal of Nuclear Medicine, suggest potential clinical utility for this strategy in cancers that are typically resistant to conventional therapies.

The method uses a pair of radiolabeled agents: one for PET imaging and another for targeted radiotherapy. The imaging agent, 89Zr-DFO-zolbetuximab, binds to claudin-18.2, a biomarker recently brought into focus following FDA approval of the gastric cancer drug zolbetuximab, and enables visualization of tumors expressing the target. Its therapeutic counterpart, 177Lu-DOTA-zolbetuximab, delivers localized radiation directly to tumor cells.
To assess the approach, researchers implanted gastric and pancreatic cancer cell lines into murine models. PET scans were conducted at multiple intervals using 89Zr-DFO-zolbetuximab or a control agent. Mice then received one of several treatments, including the radiotherapeutic agent at two different dose levels.

The results showed high uptake of the imaging agent in tumors compared to controls and significant tumor reduction in mice treated with the high dose of the therapeutic compound. In most pancreatic tumor models, complete regression was observed. Importantly, no treatment-related toxicities were reported during the study.

“Claudin 18.2-based theranostics could meaningfully change patient care in two important ways,” said Dr. Shadi Esfahani, nuclear medicine physician at Massachusetts General Hospital. “First, claudin 18.2 targeted PET imaging enables noninvasive identification of patients whose tumors strongly express this target. Second, claudin 18.2 targeted radiopharmaceutical therapy has the potential to deliver highly focused radiation directly to tumor cells, leading to significant tumor shrinkage and the possibility of improved survival.”

The research team emphasized the broader implications of integrating molecular imaging and targeted therapy in oncology, pointing to the potential for more personalized and curative treatment strategies.

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