Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma.

Abstract

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-[18F] 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.

• Authors: Claudio R Scafoglio, Brendon Villegas, Gihad Abdelhady, Sean T Bailey, Jie Liu, Aditya S Shirali, W Dean Wallace, Clara E Magyar, Tristan R Grogan, David Elashoff, Tonya Walser, Jane Yanagawa, Denise R Aberle, Jorge R Barrio, Steven M Dubinett, David B Shackelford
• Journal: Science translational medicine (Sci Transl Med) Vol. 10 Issue 467 (11 14 2018) ISSN: 1946-6242 [Electronic] United States
• PMID: 30429355 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Glucose Transporter Type 1
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Glucose

Topics

• Adenocarcinoma of Lung (diagnosis, diagnostic imaging, metabolism, pathology)
• Aged
• Aged, 80 and over
• Animals
• Biological Transport (drug effects)
• Cell Differentiation
• Cell Proliferation (drug effects)
• Female
• Glucose (metabolism)
• Glucose Transporter Type 1 (metabolism)
• Humans
• Male
• Mice, SCID
• Mice, Transgenic
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Staging
• Positron-Emission Tomography
• Precancerous Conditions (metabolism, pathology)
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology)
• Survival Analysis
• Xenograft Model Antitumor Assays