Study could potentially lead to new combination treatments for early-stage lung cancers

One of the hallmarks of cancer cell development is their dependence on sugar, especially glucose, to grow and divide. Scientists have long studied how to limit or block this process that promotes tumor growth, called glycolysis, as a potentially effective strategy against cancer.

Previously, researchers at the UCLA Health Jonsson Comprehensive Cancer Center identified a specific protein sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can use to obtain glucose.

Drugs that inhibit SGLT2 have already been approved by the FDA for other conditions, and the UCLA team found that these drugs could also slow the development of lung cancer and improve survival when tested in mice, suggesting that these drugs may once again can be used to treat lung cancer.

Although inhibiting glycolysis can slow tumor growth, researchers found that it can also make cancer cells more aggressive, making the cancer more difficult to treat. This led the team to look at other resistance mechanisms in the tumors still growing while treated with SGLT2 inhibition, which could link glucose restriction and increased aggression.

Researchers found that restricting glucose in lung cancer cells caused the cells to lose their specialized characteristics, making them more aggressive. This change was related to the change in certain molecules and the way they modify the DNA structure. The research was published in the journal Cancer research

One of those molecules was alpha-ketoglutarate, which plays a crucial role in both energy metabolism and gene regulation. Decreased levels of this molecule affected the way genes are turned on and off, activating HIF1α, a transcription factor known to play a role in making cancer cells more aggressive.

This led the researchers to discover a specific set of genes, controlled by HIF1α, that could predict how aggressive cancer might be, giving doctors important information that could help make treatment decisions. The team also discovered possible ways to prevent the tumor from becoming even more distressed or greedy when deprived of nutrients.

“Although we need to further explore the intricacies of this mechanism, our findings point to a potential therapeutic strategy using a combination of treatments with epigenic modulators or HIF inhibitors to counteract the unintended effects of glucose restriction,” said senior author of the study. Claudio Scafoglio, assistant professor of pulmonary and critical care medicine at UCLA and member of the UCLA Health Jonsson Comprehensive Cancer Center.

This study provides crucial insights into the role of glucose restriction in causing an aggressive phenotype in lung cancer. The discovery suggests a new possible combination approach to treating early-stage lung cancer, using a glucose inhibitor and an epigenetic inhibitor already available for other conditions that could help reduce tumor growth and offset aggressive behavior. More work is being done to find the right approach to prevent starvation-induced de-differentiation without causing significant side effects.