UCLA researchers in the Division of Pulmonary Medicine at the School of Medicine uncovered a novel mechanism by which cancer cells adapt to glucose restriction and develop treatment resistance, and have in response developed a novel combination therapy to delay lung adenocarcinoma development while circumventing the development of aggressive behavior and drug resistance in lung cancer.
BACKGROUND: Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide. According to statistics from the American Cancer Society, lung cancer egregiously causes more than 350 deaths a day in the U.S. Increased utilization of glucose is a hallmark of cancer, as the malignant tumor rewires metabolic pathways and requires greater energy production for macromolecule synthesis. Glucose restriction, either by blocking glucose transporters or inhibiting glycolysis, is a popular metabolic strategy in anti-tumor therapies. Previously, the Scafoglio group at UCLA discovered that SGLT2 inhibitors can significantly delay LUAD development in early stage lung cancer by depriving cells of glucose. However, further research has uncovered that SGLT2 inhibitors can induce adaptations in LUAD cells, leading to more aggressive phenotypes and resistance to therapy. Thus, combination therapies that prevent aggressive behavior could enhance the potency of SGLT2 inhibitors in treating early stage lung cancer.
INNOVATION: UCLA researchers led by Dr. Claudio Scafoglio in the Department of Pulmonary Medicine have designed a metabolic strategy to use in combination with SGLT2 inhibitors to treat early stage lung cancer. In lung cancer cell lines treated with glucose deprivation, the researchers used western blot analysis and RT-PCR to characterize the molecular mechanisms behind the adaptations seen in LUAD cells after SGLT2 inhibition and found a protein that leads to de-differentiation of LUAD cells, preventing development of resistance. They show that combination treatment with a SGLT2 inhibitor and an epigenetic inhibitor that targets and upregulates the identified protein significantly improves the response of lung cancer to SGLT2 inhibitors in a genetically engineered murine model. The novel pathway that they uncovered could have huge implications in improving care and treatment of lung cancer, particularly in the early stages.
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The pharmaceutical inhibition of SGLT2 was validated in murine models in a previous publication and patent. The researchers successfully demonstrated delay of lung adenocarcinoma development using the combination therapy in in vivo murine models.
Related Papers (from the inventors only):
Saggese, P., Pandey, A., Fung, E., Giurato, G., Weisz, A., Dubinett, S. M., & Scafoglio, C. (2022). Glucose deprivation promotes lung adenocarcinoma de-differentiation due to unbalanced EZH2 activity. Cancer Research, 82(12_Supplement), 3033-3033.
Scafoglio, C. R., Villegas, B., Abdelhady, G., Bailey, S. T., Liu, J., Shirali, A. S., ... & Shackelford, D. B. (2018). Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Science translational medicine, 10(467), 5933.
KEYWORDS: Glucose deprivation, lung cancer, cancer, de-differentiation, EZH2, HIF1a, SGLT2 inhibitors, glucose transport, epigenetic signature, metabolism