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

  • Author(s): Scafoglio, Claudio R
  • Villegas, Brendon
  • Abdelhady, Gihad
  • Bailey, Sean T
  • Liu, Jie
  • Shirali, Aditya S
  • Wallace, W Dean
  • Magyar, Clara E
  • Grogan, Tristan R
  • Elashoff, David
  • Walser, Tonya
  • Yanagawa, Jane
  • Aberle, Denise R
  • Barrio, Jorge R
  • Dubinett, Steven M
  • Shackelford, David B
  • et al.
The data associated with this publication are in the supplemental files.
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.

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