UCLA study may help explain why certain liver tumors return after thermal ablation

A new study led by investigators at the UCLA Health Jonsson Comprehensive Cancer Center may help explain why certain liver tumors return quickly after thermal ablation, a widely used minimally-invasive, image-guided technique that kills cancer cells by applying intense heat through a needle-like probe.

The team found that the sugar-binding protein Galectin-1 (Gal-1) plays a critical role in helping hepatocellular carcinoma, the most common form of primary liver cancer, resist thermal ablation and even thrive after being treated with high heat. 

"We found that Gal-1 fuels cancer cells by boosting their ability to produce energy through sugar metabolism, allowing them to resist the effects of thermal stress," said Dr. Jason Chiang, assistant professor of Radiological Sciences at the David Geffen School of Medicine at UCLA and senior author of the study. "It facilitates production of the additional energy required for liver cancer cells to continue growing, even after being exposed to thermal ablation. This helps the cells not only bounce back quickly after ablation but progress even faster on follow up imaging."

The discovery, published in Hepatology, points to a promising new strategy that involves targeting Gal-1 to block the cancer's survival mechanism. This combined approach could enhance the effectiveness of thermal ablation for people with early-stage, non-resectable liver cancer, and reduce the risk for progression after treatment. 

While ablation typically destroys cancer cells at the center of the treated area and can be curative, up to 40% of patients eventually experience cancer recurrence, often at the tumor's edge where the heat is less intense.

We've long known that the center of the tumor is destroyed by ablation, but the edges often remain vulnerable. What we didn't fully understand was how some of these peripheral cancer cells managed to resist the peri-ablational heat, but we now know that Gal-1 seems to play a critical role in helping them survive and continue growing."

Tu Nguyen, medical student at the David Geffen School of Medicine at UCLA, and first author of the paper

To better understand how Gal-1 works and influences liver cancer treatment, researchers analyzed 58 treatment naïve pre-ablation biopsy samples from patients with early-stage liver cancer and subsequently found to have either responded or had local recurrences to the ablation treatment. Using advanced lab techniques to analyze protein profiles of the pre-ablation biopsy samples, they found Gal-1 to be overproduced in tumors that had rapid recurrence after thermal ablation.

Using patient biopsy samples, genetically modified cell cultures and mouse cancer models, the researchers showed that Gal-1 enhances cancer cells' ability to use sugar through a process called glycolysis, even in the face of thermal stress. They also found Gal-1 helps feed another major energy-producing system in cells, known as the tricarboxylic acid (TCA) cycle. Together, these metabolic pathways provide a survival advantage for tumor cells with higher Gal-1 levels after exposure to sublethal heat found in ablation zone peripheries, allowing them to quickly regrow after ablation.

While Gal-1 has previously been linked to cancer spread and resistance to therapy in other tumor types, this study is among the first to connect liver cancer recurrence to a specific metabolic mechanism driven by Gal-1, the researchers noted.

To test a potential pharmaceutical solution, the team paired thermal ablation with a drug that blocks Gal-1, called OTX008. This is a small-molecule inhibitor that binds selectively to Gal-1 to disrupt its function within tumor cells. When tested in mice, the combined treatment approach led to a 2-fold reduction in tumor size and a significant decrease in cancer cells' ability to produce energy, compared to either treatment alone. These effects were closely linked to lower levels of the Gal-1 protein in tumors treated with the combination therapy, suggesting that Gal-1 inhibition could sensitize liver tumors to ablation and reduce recurrence risks. 

"By blocking Gal-1, we're not just making standard-of-care thermal ablation work better in early-stage liver cancer, but we may also be opening doors to better treatment options across all stages of liver cancer," said Chiang. "Gal-1 is an evolutionarily conserved protein that is utilized in not only cancer metabolism, but also in immunology and cancer signaling pathways. There is thus tremendous potential in disrupting Gal-1 to also improve response rates of current drugs that are normally used to treat advanced stage liver cancers."

While more studies are needed to confirm the results in human patients, the research shows considerable clinical promise for improving patient outcomes. The discovery not only identifies a key metabolic driver of liver cancer recurrence but also introduces a potential new therapeutic target. By integrating Gal-1 inhibition into existing treatment strategies, clinicians may be able to eliminate residual tumor cells, reduce recurrence rates and potentially extend this benefit to more advanced stages of the disease.

Other authors of this study, all from UCLA, are Yonghwan Shin, Aravinth Ruppa, Abigail Krall, Janet Pham, Po-Chun Chen, Hannah Mirmohammadi, Pedram Keshavaraz, Richard Finn, Vatche Agopian, Samuel French, Heather Christofk, David Lu and Steven Raman.

The work was supported in part by the UCLA Department Exploratory Research Grant, the UCLA Health Jonsson Comprehensive Center Fellowship Grant, and the Radiological Society of North America Research Scholar Grant.