Novel Use of SGLT-2 Inhibitors for Treatment of Early-Stage Lung Adenocarcinoma

Study assessed association of cancer and sodium glucose transporter 2 expression as well as potential benefit of SGLT-2 treatment.

The leading cause of cancer-related mortality is a variant of lung cancer known as non-small cell lung cancer (NSCLC). For those with early stages, its 5-year survival rate is roughly 55.6%; however, the survival rate decreases to 4.5% once the disease has metastasized. Consequently, a large amount of research efforts has been focused on methods to identify cancer in its earlier stages and prevent progression to the later stages of lung cancer. The most frequently occurring variants of NSCLC are lung adenocarcinoma (LADC) and squamous cell carcinoma (SqCC). SqCC typically affects the respiratory epithelial cells located in the large airways, which can be easily accessed via bronchoscopy. LADC typically occurs in alveoli and smaller bronchioles, thus making assessment more difficult. This research focuses the LADC variant as it is more difficult to assess.

A commonality between most types of cancer is the increased need of glucose for cancerous cells. Typically, cancerous glucose metabolism can be assessed via positron emission tomography (PET) scans. These scans allow for the visualization of glucose uptake by using a glucose analog known as fluoro-D-glucose (FDG). This imaging method works well for advanced LADC but is unable to identify precancerous or early LADC tumor growths. It was thought that this shortcoming of the PET scan was due to lower glucose requirements of pre and early cancerous cells. However, recent research into other types of cancer indicates that different glucose transporters are expressed during the pre and early stages compared to the later stages. FDG is readily transported by the GLUT glucose transporter that is expressed by the cancer cell during the later stages of LADC. It was noted in previous studies of pancreatic and prostate cancers that sodium glucose transporter 2 (SGLT2) was expressed early on. In an effort to determine if this is also true with LADC, tissue samples of various stages of cancerous growth were tested for SGLT2 and GLUT1 glucose transporters via immunohistochemistry staining. It was determined that SGLT2 was expressed preferentially in early stages of tumor growth and GLUT1 was preferentially expressed during the later stages of tumor growth.

Considering FDG is not actively transported by the SGLT2 glucose transporters, it would stand to reason that PET scans utilizing FDG would be unable to detect pre or early stage LADC. When methyl 4-deoxy fluoro-alpha-D-glucopyranoside or Me4FDG (a PET tracer that is specifically transported by SGLT2) was used, pre and early stage LADC were able to be detected in study mice prior to progression.

Considering that pre and early stage LADC preferentially express SGLT2 for glucose transport, it was hypothesized that SGLT2 inhibition may decrease progression. This was tested via inducing tumor growth in test mice, and then treating them with either placebo or 30 mg/kg of canagliflozin daily for up to 3 months. It was found that the treatment group exhibited a significant survival benefit and reduced tumor burden over the placebo group; however, tumor growth in the intervention group eventually escaped SGLT2 inhibition, possibly due to SGLT2 transporter upregulation.

The results of this study illustrate that in pre or early stages of LADC, glucose is taken up into the cancerous cell predominantly by SGLT2 transporters. As the cancer progresses, glucose uptake is shifted to GLUT1 transporters. Furthermore, this study shows that Me4FDG PET scans can be used to visualize glucose metabolism in early LADC and thus can aid in clinical monitoring. The results of the SGLT2 inhibition experiment are not as clinically significant at this time. Inhibition did produce a survival benefit and reduced tumor burden in study mice, but the effect was not durable. Further study is needed to determine the relevance of this finding.

Practice Pearls:

• In pre and early stages of LADC, transport of glucose into cancerous cells is facilitated predominantly by SGLT2 glucose transporters. As the cancer progresses, transport of glucose shifts toward GLUT1 transporters.
• Me4FDG PET scans can be used to assess glucose metabolism in pre and early LADC cells.
• SGLT2 inhibition appears to provide some benefit in test mice; however, further testing is required to determine its clinical significance.

Reference:

Scafoglio, Claudio R., et al. “Sodium-Glucose Transporter 2 Is a Diagnostic and Therapeutic Target for Early-Stage Lung Adenocarcinoma.” Science Translational Medicine, American Association for the Advancement of Science, 14 Nov. 2018, stm.sciencemag.org/content/10/467/eaat5933.full.

Michael Zaccaro, Pharm. D. Candidate 2019, LECOM School of Pharmacy