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 potential as a novel and impactful targeted therapy for this aggressive subtype of gastric signet ring cell carcinoma. Conclusions: This preliminary study supports the further development of PVR-DXd as a candidate therapy for advanced GSRCC.
背景：胃印戒细胞癌（GSRCC）是胃癌的一种独特亚型，具有独特的生物学特征，导致早期诊断率低、预后差，以及对化疗和免疫疗法的反应有限。针对GSRCC的有效靶向疗法仍然稀缺。鉴于这些治疗挑战以及抗体药物偶联物（ADCs）在临床中的潜在疗效，本研究致力于识别具有显著潜力的新型ADCs，以改善GSRCC的治疗效果。方法：我们利用多组学数据（包括转录组学和蛋白质组学）对GSRCC进行了全面的生物信息学分析，并确定脊髓灰质炎病毒受体（PVR）作为GSRCC的潜在治疗靶点。我们选择deruxtecan（DXd）作为开发靶向GSRCC的ADC的有效载体。合成的PVR单克隆抗体-DXd复合物（PVR-DXd）的药物抗体比（DAR）为4。结果：PVR-DXd在人类GSRCC异种移植模型中表现出强大的抗肿瘤活性，有效消除肿瘤的同时不影响正常组织，突显了其作为这种侵袭性胃印戒细胞癌亚型的新型且具有影响力的靶向疗法的潜力。结论：这项初步研究支持进一步开发PVR-DXd作为晚期GSRCC的候选疗法。
肿瘤(癌症)患者之家