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Eva Jolanthe Koziolek



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    P1.11 - Screening and Early Detection (ID 177)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.11-14 - SGLT2 Is a Diagnostic and Therapeutic Target for Early-Stage Lung Adenocarcinoma (ID 2854)

      09:45 - 18:00  |  Author(s): Eva Jolanthe Koziolek

      • Abstract
      • Slides

      Background

      Early diagnosis of lung adenocarcinoma (LUAD) is crucial. 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 premalignancy 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.

      Method

      We have recently discovered that premalignant ad early invasive lesions of the LUAD spectrum rely on sodium-glucose transporter 2 (SGLT2) for glucose uptake, whereas advanced carcinomas up-regulate transporters of the GLUT family. This is consistent with the observation that positron emission tomography (PET) with 2-[18F] fluorodeoxyglucose (FDG), which detects GLUT but not SGLT activity, is a standard tool for staging advanced disease, but has low sensitivity for early-stage LUAD. We measured SGLT2 activity in vivo with the PET tracer methyl-4-[18F] fluorodeoxyglucose (Me4FDG).

      Result

      Me4FDG detects early-stage, FDG-negative LUAD in mouse models and in patients. Importantly, Me4FDG uptake correlates with tumor growth rate in patient-derived LUAD xenografts (fig. 1). 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 LUAD.

      Fig. 1. Me4FDG PET detects early lung adenocarcinoma and predicts growth rate. A) Time course of Me4FDG and FDG imaging in genetically engineered mice with LUAD. The early time point was taken when tumor nodules reached an average diameter of 7 mm (left panels), and the advanced time point was performed on the same mice 1 month later (right panels). B) Representative image of Me4FDG PET/CT imaging in mice carrying patient-derived LUAD xenografts. C) Correlation between Me4FDG uptake in the patient-derived xenografts and the fold increase in volume in a 1-month period following the PET/CT scan.fig.1.jpg

      Conclusion

      SGLT2 is a promising biomarker not only to diagnose early-stage tumors by PET imaging, but also to predict response to SGLT2 inhibitors.

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    P2.11 - Screening and Early Detection (ID 178)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.11-39 - Multimodal Monitoring of Patient-Derived Early-Stage Lung Adenocarcinoma with the Chicken Chorioallantoic Membrane System   (ID 2827)

      10:15 - 18:15  |  Presenting Author(s): Eva Jolanthe Koziolek

      • Abstract

      Background

      Positron-emission-tomography (PET), imaging uptake of [18F] fluorodeoxyglucose (FDG), is a powerful tool for lung cancer staging, but lacks sensitivity in early lesions. We have recently discovered that early-stage lung adenocarcinoma (LUAD) depends on another system for glucose uptake, the sodium- glucose transporter 2 (SGLT2), not detected by FDG PET. The tracer methyl 4-[18F] fluorodeoxyglucose (Me4FDG) is specific for SGLTs.

      Because the establishment of patient-derived xenografts (PDXs) from early-stageLUAD is characterized by low efficiency and long experimental times, we have developed an alternative model to study tumor metabolism in LUAD, based on the implantation of tumor tissue on the chorioallantoic membrane (CAM) of chicken eggs (in ovo system).

      Method

      PDXs of LUAD were established in ovo by implanting tumor fragments or dissociated cells in matrigel onto the CAM of fertilized chicken eggs. Xenografts were grown for up to 10 days. After day 7, the eggs were imaged with FDG and Me4FDG PET to characterize glucose uptake, then rescanned with both tracers after treatment with SGLT2 inhibitor dapagliflozin to prove SGLT2 specificity of Met4FDG. Multiparametric magnetic resonance imaging (MRI) was performed to assess tumor growth, morphology (T1w, T2w, diffusion-weighted imaging) and vasculature (angiography; GadospinP). At day 10, the xenografts were harvested for histology and immunohistochemistry or reimplanted onto a new CAM for continuous passaging.

      Result

      FDG- and Me4FDG-PET adenocarcinomas confirmed the presence of both glucose transporters, GLUT1 and SGLT2. MRI angiography revealed that both tumor plaques and tumor fragments were connected to the embryonic vasculature. Following dapagliflozin treatment, Met4FDG uptake was successfully blocked in the PD tumor fragments.

      Conclusion

      The CAM xenograft model is useful for studying the heterogeneity of glucose uptake in ovo by imaging the activity of different transporters with FDG and Me4FDG. The novel PET tracer Met4FDG allows to validate SGLT2 expression as well as its blockage by SGLT2 inhibitors gliflozins.