Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Sci Transl Med. 2018 Nov 14;10(467). doi: 10.1126/scitranslmed.aat5933.
The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium-dependent glucose transporter 2 (SGLT2), whose activity identified metabolically active lung premalignancy and early-stage lung adenocarcinoma (LADC). We found that SGLT2 is expressed early in lung tumorigenesis and is found specifically in premalignant lesions and well-differentiated adenocarcinomas. SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl 4-deoxy-4-[F] fluoro-alpha-d-glucopyranoside (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry and Me4FDG PET, we identified high expression and functional activity of SGLT2 in lung premalignancy and early-stage/low-grade LADC. Furthermore, selective targeting of SGLT2 with FDA-approved small-molecule inhibitors, the gliflozins, greatly reduced tumor growth and prolonged survival in autochthonous mouse models and patient-derived xenografts of LADC. Targeting SGLT2 in lung tumors may intercept lung cancer progression at early stages of development by pairing Me4FDG PET imaging with therapy using SGLT2 inhibitors.
肺结节的诊断定义为恶性或良性，这对临床医生来说是一个重大挑战。我们发现了一个潜在的标志物，即钠依赖性葡萄糖转运蛋白 2（SGLT2），其活性可以识别代谢活跃的肺癌前病变和早期肺腺癌（LADC）。我们发现 SGLT2 在肺癌发生的早期表达，并特异性存在于癌前病变和高分化腺癌中。SGLT2 的活性可以通过正电子发射断层扫描（PET）用示踪剂甲基 4-脱氧-4-[F]氟-α-D-吡喃葡萄糖苷（Me4FDG）检测到，Me4FDG 特异性检测 SGLT 活性。我们通过免疫组织化学和 Me4FDG PET 的组合，在肺前病变和早期/低级别 LADC 中鉴定出 SGLT2 的高表达和功能活性。此外，用 FDA 批准的小分子抑制剂，即格列净，选择性靶向 SGLT2，可显著减少自发小鼠模型和 LADC 患者来源异种移植物中的肿瘤生长并延长生存期。通过将 Me4FDG PET 成像与 SGLT2 抑制剂治疗相结合，靶向 SGLT2 可能会在肺癌发展的早期阶段拦截癌症进展。
