Abstract

Simple SummaryGastric signet ring cell carcinoma is a rare and aggressive form of stomach cancer that responds poorly to existing treatments. Many patients are diagnosed at an advanced stage and have limited therapeutic options. In this study, we analyzed cancer tissue at multiple molecular levels and identified a surface protein called the poliovirus receptor (PVR) as a promising target for new therapy. We then developed an antibody-drug conjugate (ADC) that links an antibody against PVR to a potent chemodrug, allowing the ADC to be delivered selectively into cancer cells. In animal models that closely mimic human disease, this targeted therapy strongly suppressed tumor growth while sparing normal tissues. Our findings suggest that this strategy may offer a more effective and safer treatment option for patients with this difficult-to-treat stomach cancer.Background: Gastric signet-ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer characterized by unique biological features, leading to low rates of early diagnosis, poor prognosis, and limited response to chemotherapy and immunotherapy. Effective targeted therapies for GSRCC remain scarce. Given these treatment challenges and the potential efficacy of antibody-drug conjugates (ADCs) in clinical settings, this study focuses on identifying novel ADCs with significant potential to improve the treatment outcomes of GSRCC. Methods: We conducted a comprehensive bioinformatics analysis of GSRCC using multi-omics data (including transcriptomics and proteomics) and identified the poliovirus receptor (PVR) as a potential therapeutic target for GSRCC. We selected deruxtecan (DXd) as an effective carrier for developing an ADC targeting GSRCC. The synthesized PVR monoclonal antibody-DXd complex (PVR-DXd) has a drug-to-antibody ratio (DAR) of 4. Results: PVR-DXd demonstrated potent antitumor activity in a human GSRCC xenograft model, effectively eliminating tumors while sparing normal tissue, highlighting its po