130 - Overcoming Resistance to Thermal Ablation in Hepatocellular Carcinoma via Galectin-1 Targeting: A Murine Preclinical Investigation

Purpose: Thermal ablation is the standard-of-care treatment modality with curative intent for early-stage nonresectable HCC, but a durable response is limited, with up to 40% of patients with HCC eventually experiencing local recurrence on posttreatment surveillance. While ablation causes immediate cell death, its metabolic impact on surrounding tissue is unclear. We aimed to identify protein profiles in patients with HCC that are responsive or resistant to thermal ablation and demonstrate the therapeutic potential of combining Galectin-1 (Gal-1) inhibition with thermal ablation using a murine model.

Materials and Methods: We performed proteomic analysis on pre-ablation biopsies from 32 responsive and 23 non-responsive HCC patients. Separately, we evaluated the Gal-1 inhibitor OTX008 in an orthotopic mouse model of HCC. SNU449 cell-derived tumors were treated with OTX008 (5 mg/kg IP, twice weekly) for two weeks before and one week after microwave ablation. One-week post-ablation, tumors were harvested for weight and metabolic analysis

Results: In our proteomic analysis of patient biopsy samples, we found a statistically significant 1.5-fold increase in Galectin-1 in non-responsive (n=23) vs. responsive (n=32) hepatocellular carcinoma patients based on proteomic analysis of pre-ablation biopsies (p< 0.01).





In the mouse model, combining the Galectin-1 inhibitor with thermal ablation led to a significant 2-fold reduction in tumor size (n=5). This was compared to both the control group (n=7) and the group that received only thermal ablation (n=7), with the results being statistically significant (p< 0.05).





Further metabolic analysis of these tumors revealed a substantial 40% decrease in galactose and a subsequent 60% decrease in galactose-1 phosphate within the combination therapy group compared to thermal ablation alone group (p< 0.001). This disruption in a key metabolic pathway resulted in an 80% decrease in overall energy production, as indicated by corresponding decreases in the TCA cycle metabolites, citrate (p< 0.01) and malate (p< 0.001).

Conclusion: Galectin-1 plays a crucial role in thermal ablation resistance in HCC. Therefore, targeting this protein in conjunction with thermal ablation significantly increased the therapy's effectiveness, suggesting a novel synergistic strategy to improve patient outcomes.