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Lung cancer is the leading cause of cancer-related death worldwide; new diagnostic and therapeutic strategies are urgently needed. The technological advancement of diagnostic tools such as computed tomography (CT) and the implementation of nation-wide screening programs has improved the survival of high-risk individuals, specifically smokers. However, CT leads to the identification of many lung nodules that are not malignant, most of which will regress spontaneously or after a short course of anti-bacterial or anti-inflammatory treatment. These lesions are reason for anxiety for the patients and represent a diagnostic challenge for the clinicians, who need to take an important decision between watchful waiting and surgical removal of these lesions. Positron-emission tomography (PET) is a powerful imaging technique that exploits cancer cell avidity for sugar to monitor uptake of a radioactive glucose analog, 2-[18F] fluoro-deoxyglucose (FDG), in neoplastic tissue, and is standard for NSCLC staging. However, FDG-PET fails to detect early and pre-neoplastic lesions, and is not currently used for diagnosis of lung nodules. We have recently discovered that early lung tumors have a novel system for glucose import, not detected by FDG: the sodium-dependent glucose transporters (SGLTs). The activity of SGLTs can be imaged with a novel tracer, methyl 4-[18F] fluorodeoxyglucose (Me4FDG). We have found that sodium-dependent glucose transporter 2 (SGLT2) plays a crucial role in early stages of NSCLC development in a mouse model, and is expressed in human pre-neoplastic lesions. Treatment of early-stage tumors with SGLT2 inhibitors significantly slows down tumor growth and prolongs survival in mice. Therefore, we propose to study in detail the functional role of SGLT2 in early lung carcinogenesis, with Me4FDG PET imaging and therapeutic trials with SGLT2 inhibitors both in genetic mouse models and in patient-derived tumors implanted in mice; moreover, we are going to investigate SGLT2 presence in pre-malignant and early-stage human lung adenocarcinoma samples. With these experiments, we will address the following questions: 1) Is SGLT2 activity an early marker of NSCLC? 2) Is SGLT2 inhibition an effective treatment against early-stage NSCLC? The proposed research has the potential to introduce a novel diagnostic tool for early diagnosis of lung cancer. Moreover, Me4FDG PET could identify pre-neoplastic lesions that may be targeted with SGLT2 inhibitors to block their progression to lung cancer. These findings can be quickly translated into the clinical practice; our collaborator, Dr. Barrio, has a pending Investigational New Drug application with the FDA for the use of Me4FDG in cancer patients. Moreover, SGLT2 inhibitors have already been approved by the FDA for the treatment of diabetes, and could be re-purposed for the treatment of lung cancer.
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