Repurposed FDA-approved agents for hepatic artery infusion in colorectal liver metastases

Colorectal cancer (CRC) remains a leading cause of cancer-related death, with liver metastases (CRLM) representing the most common cause of mortality. Despite advances in systemic therapy, outcomes for patients with CRLM remain poor, underscoring a critical need for improved, liver-directed treatment strategies. Hepatic artery infusion (HAI) pumps are an effective method to deliver high local concentrations of chemotherapy directly to the liver while limiting systemic toxicity. The currently-standard of care compounds for HAI have limited efficacy and elevated hepatotoxicity, emphasizing the demand for treatment regimens that have better patient outcomes. In this project, we explored a drug repurposing strategy by evaluating FDA-approved chemotherapeutic agents with pharmacokinetic properties compatible with HAI delivery. Drugs were selected using established pharmacokinetic databases and then tested in vitro using CRC cell models and a normal epithelial liver cell line to assess cytotoxicity and dose-response. In addition, we investigated the therapeutic potential of combining a microtubule destabilizer with an FDA-approved fatty acid synthase (FASN) inhibitor. Synergy experiments demonstrated enhanced cytotoxic effects when chemotherapeutics were combined with the FASN inhibitor, suggesting that there is potential for a novel treatment regimen for patients presenting with this disease. These preliminary findings support drug repurposing within the context of HAI delivery as a clinically translatable approach. By utilizing existing FDA-approved compounds of both chemotherapeutic agents and metabolic inhibitors, this strategy may lay the groundwork for novel therapies for patients with CRLM. Further preclinical and translational studies will be necessary to define optimal drug combinations and dosing regimens, with the ultimate goal of expanding therapeutic options and improving outcomes for this high-risk patient population.