Novel Theranostic Model Shows Curative Potential for Gastric and Pancreatic Tumors

A newly developed radiopharmaceutical pair can precisely detect and effectively treat--completely eradicating tumors in certain preclinical models--gastric and pancreatic tumors. Targeting the well-defined and accessible biomarker claudin-18.2, the theranostic technique has the potential to move the field substantially closer to durable disease control and potentially cure--in otherwise difficult-to-treat solid tumors. This research was published in the January issue of The Journal of Nuclear Medicine.

Advanced upper gastrointestinal cancers, including esophageal, gastric, and pancreatic cancer, are among the deadliest cancers worldwide, accounting for one-third of all cancer deaths. Patients have very limited treatment options, especially in advanced stages, and current therapies provide only modest improvements in survival. As such, there is a critical unmet need for more effective and more precise approaches.

"Claudin-18.2 recently gained clinical attention following U.S. Food and Drug Administration approval of the gastric cancer treatment zolbetuximab, which targets the biomarker," said Shadi Esfahani, MD, MPH, nuclear medicine physician at Massachusetts General Hospital in Boston. "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."

To evaluate the theranostic pair, preclinical murine models were developed with both pancreatic and gastric cancer cell lines. Serial PET imaging with ⁸⁹Zr-DFO-zolbetuximab or ⁸⁹Zr-DFO-IgG as a control was performed at one, three, and six days, followed by ex vivo analysis of biodistribution. Next, tumor-bearing mice received a single intravenous injection ¹⁷⁷Lu-DOTA-zolbetuximab (high or low dose), non-radiolabeled zolbetuximab, ¹⁷⁷Lu-DOTA-IgG, ¹⁷⁷Lu-DOTA, or saline as a treatment. Effectiveness and toxicity of the treatments were evaluated by laboratory and histologic analyses.

Serial PET imaging demonstrated a high tumor uptake of ⁸⁹Zr-DFO-zolbetuximab at all timepoints--significantly higher than the uptake seen in mice imaged with control ⁸⁹Zr-DFO-IgG. High-dose ¹⁷⁷Lu-DOTA-zolbetuximab resulted in reduced tumor growth in gastric and pancreatic mice models, with complete regression of most pancreatic tumors. No radiation-induced toxicities were observed during the study.

"Claudin 18.2 based theranostics could meaningfully change patient care in two important ways," noted Esfahani. "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."

She continued, "More broadly, the study underscores how advances in biomarker discovery, radiopharmaceutical development, and patient selection are bringing the field closer to treatments with curative potential rather than incremental benefit. As additional tumor-specific targets are identified and validated, molecular imaging-guided theranostics could increasingly enable personalized, highly effective, and safer cancer treatments, positioning nuclear medicine at the forefront of next-generation oncology."

Figure 2: Evaluation of [⁸⁹Zr]Zr-DFO-zolbetuximab PET specificity in mouse models of GCa over multiple time points. (A and B) Maximum-intensity-projection serial PET/CT images for male nude mice implanted with GSU gastric tumors (white circles) imaged with [⁸⁹Zr]Zr-DFO-zolbetuximab or [⁸⁹Zr]Zr-DFO-IgG 1, 3, and 6 d after injection. (C and D) Quantitative in vivo biodistribution of [⁸⁹Zr]Zr-DFO-zolbetuximab and [⁸⁹Zr]Zr-DFO-IgG in tumor and selected tissues. ns = not significant on one-way ANOVA test.

The authors of "Claudin 18.2 as a Biomarker for Imaging and Radiopharmaceutical Therapy in Gastric and Pancreatic Tumors" include Shvan J. Raheem, Santosh Bashyal, Arvin Haj-Mirzaian, Youself Khazaei Monfared, Umar Mahmood, Pedram Heidari, and Shadi A. Esfahani, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Matthew R. Strickland, David T. Ting, and Samuel J. Klempner, Division of Hematology Oncology, Mass General Brigham Cancer Institute, and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Benjamin M. Larimer, Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama.

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