Abstract A16: Sodium-dependent glucose transporter 2 is a novel diagnostic and therapeutic target for early-stage lung adenocarcinoma
Authors: Scafoglio Claudio , Bailey Sean T. , Abdelhady Gihad , Liu Jie , Yanagawa Jane , Shirali Aditya , Wallace Dean W. , Barrio Jorge R. , Wright Ernest M. , Walser Tonya , Dubinett Steven M. , Shackelford David B. 
Published: February 2019

Abstract
Lung cancer claims approximately 160,000 lives in the United States every year, and lung adenocarcinoma (LADC) is the most frequent type. Early diagnosis is crucial; the National Lung Screening Trial showed a 20% reduction in mortality in high-risk individuals screened by computed tomography (CT). However, CT has low specificity in early-stage LADC. In vivo detection of glucose uptake by FDG PET is a standard tool for lung cancer staging, but has low sensitivity in early-stage LADC. Here, we demonstrate that GLUT transporters, responsible for FDG uptake, are expressed in advanced, poorly differentiated LADC, whereas early LADC utilizes a different glucose transport system, the sodium-dependent glucose transporter 2 (SGLT2), that is not detected by FDG. This can be imaged with the novel tracer Me4FDG.
We investigated the expression of two different glucose transporters, GLUT1 and SGLT2, in a cohort of 56 human LADC specimens, in patient-derived xenografts, and in a KrasG12D-driven, p53-null genetically engineered mouse model of LADC. We observed a switch in the modality of glucose transport during lung carcinogenesis: SGLT2 was highly expressed in premalignant lesions and well-differentiated LADC, whereas GLUT1 was upregulated in advanced, poorly differentiated lesions. This pattern was observed both in human samples and in murine models. This observation led us to hypothesize that early-stage LADCs are often negative on FDG PET because this imaging modality does not detect the activity of SGLT2, which is expressed in early lesions. Therefore, we performed PET imaging with the tracer Me4FDG, which measures SGLT2 activity, in our mouse model, and observed that Me4FDG accumulated in small nodules that were negative with FDG. We confirmed the functionality of SGLT2 in human LADC by Me4FDG PET in patient-derived xenografts. Finally, we tested the hypothesis that sodium-dependent glucose transport is a critical metabolic supply strategy in the early stages of lung adenocarcinoma development. We performed therapeutic trials in genetically engineered mouse models with the FDA-approved SGLT2 inhibitor canagliflozin, which slowed down tumor progression and prolonged mouse survival, by specifically reducing the proliferation rate of premalignant lesions.
In conclusion, Me4FDG PET is a novel diagnostic test to image lung premalignancy and early-stage LADC. We propose that Me4FDG-PET will identify the patients who are likely to respond to SGLT2 inhibition, as a cancer interception strategy to prevent the progression of premalignancy to invasive disease, by blocking the supply of glucose required for proliferation of premalignant lesions.
Citation Format: Claudio Scafoglio, Sean T. Bailey, Gihad Abdelhady, Jie Liu, Jane Yanagawa, Aditya Shirali, Dean W. Wallace, Jorge R. Barrio, Ernest M. Wright, Tonya Walser, Steven M. Dubinett, David B. Shackelford. Sodium-dependent glucose transporter 2 is a novel diagnostic and therapeutic target for early-stage lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A16.