The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium 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 pre-malignant lesions and well-differentiated adenocarcinomas. Of note, SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl-4-[18F] fluorodeoxyglucose (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.

Center at UCLA. ONW and CGR are inventors on a patent held by the University of California Regents that discloses 18 F-FAC. There are no other potential conflicts of interest.

Objective: To explore the presence of small airway disease (SAD) and emphysema in scleroderma-related interstitial lung disease (SSc-ILD) and to evaluate the physiologic and clinical correlates of SAD in SSc-ILD. Methods: Thoracic high-resolution computed tomography (HRCT) images obtained from the Scleroderma Lung Study II (SLSII) participants were reviewed by a group of thoracic radiologists. The presence of SAD was assessed by visual assessment for air trapping. HRCT scans were also evaluated for the presence of emphysema. The association of the presence of air trapping and emphysema with physiological measures of airway disease and clinical variables was evaluated. Results: A total of 155 baseline HRCT scans were reviewed. For assessment of air trapping, images needed to be adequate end-expiratory examinations, leaving 123 scans. Air trapping was seen in 13/123 (10.6%) of the SSc-ILD cohort and was independent of smoking history, asthma or the presence of gastroesophageal reflux. Air trapping on HRCT was not associated with physiologic evidence of SAD. We also identified 8/155 (5.2%) patients with emphysema on HRCT, which was independent of SAD and found mostly in prior smokers. Conclusion: We report the first study of air trapping on standardized, high-quality HRCT images as a reflection of SAD in a relatively large, well characterized SSc-ILD cohort. The presence of SAD in non-smoking SSc-ILD patients supports that SSc may cause not only restrictive lung disease (SSc-ILD), but also, to a lesser extent, obstructive disease. Physiologic measures alone may be inadequate to detect airway disease in patients with SSc-ILD.

Lung cancer is the leading cause of cancer-related death, and lung adenocarcinoma (LUAD) is the most frequent histology. Early diagnosis and treatment are essential; however, there are no targeted diagnostic and therapeutic approaches for early LUAD. An important hallmark of cancer is the increased glucose uptake via GLUT transporters. GLUT activity is imaged in cancer by positron emission tomography (PET) with 2-[18F] fluorodeoxyglucose (FDG). FDG PET is a standard tool for staging advanced lung cancer, but has low sensitivity for early-stage LUAD. This is considered a consequence of slow growth and low requirement of glucose. However, we discovered a novel system of metabolic supply not detected by FDG PET: the sodium glucose transporter 2 (SGLT2)1. SGLT2 activity can be measured in vivo with the PET tracer methyl-4-[18F] fluorodeoxyglucose (Me4FDG). We identified high expression of SGLT2 in human lung premalignancy and early-stage LUAD. Me4FDG detects early-stage, FDG-negative LUAD in mouse models. Targeting SGLT2 with FDA-approved inhibitors significantly reduces tumor growth and prolongs survival in genetic and patient-derived murine models, confirming an important role of SGLT2 in early-stage LUAD2. The reliance of early stage LUAD on SGLT2 opens exciting diagnostic and therapeutic opportunities. The National Lung Screening Trial showed a 20% reduction in lung cancer mortality in high risk individuals using low-dose helical computed tomography (CT). CT is highly sensitive for detecting lung nodules, but is limited by low specificity, especially for LUAD. On CT, LUAD may appear as solid or subsolid nodules. Most subsolid nodules are not cancer, and many will remain stable or resolve; however, subsolid lesions can represent premalignant lesions or adenocarcinoma in situ. These lesions in the early spectrum of LUAD may persist for months to years before transforming into invasive disease. As a result, current standard of care is to follow these patients with CT imaging to monitor these indeterminate lesions for radiologic signs of malignant progression. The identification of novel biomarkers to predict the malignant potential of these nodules at their initial identification is of paramount importance. 1Scafoglio et al. Proc Natl Acad Sci U S A 2015;112(30):E4111-4119 2Scafoglio et al. Sci. Transl. Med. 10, eaat5933 (2018) Citation Format: Brendon Villegas, Eva Koziolek, Jie Liu, W. Dean Wallace, David Elashoff, Denise R. Aberle, David B. Shackelford, Jorge R. Barrio, Jane Yanagawa, Steven M. Dubinett, Claudio Scafoglio. SGLT2 is a diagnostic target for early stage lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4224.

Background: Lung adenocarcinoma (LUAD) leads to majority of lung cancer deaths. Various somatic mutations and copy number variations have been reported in LUAD, but their relevance to clinical prognosis of early stage LUAD is poorly understood. Besides, nearly 30% of patients with stage IA NSCLC eventually die of recurrence or metastasis in spite of the use of standard staging procedures. This study was designed to explore the genomic landscape in stage IA LUAD patients and find immune microenvironment features in recurrences. Method: 43 eligible stage IA LUAD patients with radical surgery and without adjuvant therapy from Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College were included in this study. Up to last follow-up in April 9th, 2018, 22 patients were relapsed and 21 were not recurrent. Clinical data were collected in the baseline data analysis. Whole-exome sequencing and RNA IO panel sequencing were performed in tumor and normal lung tissues. Result: There were no significant differences in terms of clinical and pathological features comparing recurrences to non-recurrences. The most common mutated genes were TP53(48%), EGFR (18%) and KRAS (9%). Tumor mutation burden (TMB) values ranged from 0.2 to 16.4 Mutations/Mb, with a median of 2.5Mutations/Mb. Twenty-two differential genes were screened out and classified to five signatures in terms of its function. These five signatures including tumor cell proliferation, tumor antigen, cytotoxic T cells activity, T lymphocyte chemotactic factor, and natural killer cell activation were dramatically high expressed in non-recurrences (p<0.05). Besides, cytolytic activity was significantly higher in non-recurrences (p<0.05), which were represented as the logaverage expression of GZMA and PRF1. Furthermore, six genes out of twenty-two genes were found to be significantly important in terms of disease-free survival (DFS) in stage IA LUAD with radical resection according to Kaplan-Meier analysis. However, there was no relation between TMB and DFS (p¼0.501). Conclusion: This is the first study reporting the relation of gene landscape and immune microenvironment features with prognosis in stage IA LUAD after curative resection. Host immunity is significantly related with the recurrence, whereas tumor mutation and TMB were not. Six genes related with host immunity have been found and promised to be novel prognostic factors in prognosis of stage IA LUAD.

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Conclusion: Age, smoking are risk factors related to lung cancer and positive nodules. 50 years old with a history of smoking or tuberculosis may be a high risk group for lung cancer in China.

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