Inhibition of SCD1 As a Therapeutic Strategy for Hepatocellular Carcinoma
Recent studies have implicated lipid biosynthesis and desaturation as requirements for the survival of hepatocellular carcinoma. Stearoyl CoA desaturase 1 (SCD1) is a key mediator of fatty acid biosynthesis, and it is rate limiting in the conversion of saturated fatty acids, such as palmitic acid, to monounsaturated fatty acids.
Although saturated fatty acids have been implicated in lipotoxicity, monounsaturated fatty acids can induce noncanonical autophagy, activate Wnt signaling, enhance membrane turnover and increase energy production. SCD1 can contribute to tumor cell survival through metabolic adaptations resulting from enhanced conversion of saturated fatty acids to monounsaturated fatty acids.
In preliminary studies, project researchers in the Mayo Clinic Hepatobiliary SPORE identified SCD1 protein in hepatocellular carcinoma tissues. Through a combined computational and synthetic chemistry approach, they synthesized several novel SCD1 inhibitors.
The project's lead SCD1 inhibitor, SSI-4, dose-dependently inhibited cell proliferation in hepatocellular carcinoma cell lines and demonstrated synergy with sorafenib and in vivo anti-tumor activity. SSI-4 has excellent oral bioavailability and is well tolerated with long-term daily dosing. The SCD1 blockade led to endoplasmic reticulum stress followed by apoptotic cell death.
In this project in the Hepatobiliary SPORE, researchers are evaluating SSI-4 alone and in combination with other therapies in preclinical hepatocellular carcinoma animal models, as a prelude to early-phase clinical trials for hepatocellular carcinoma. The researchers are also seeking predictive biomarkers of response that could be clinically useful.
The project researchers hypothesize that targeting the stearoyl CoA desaturase 1 (SCD1) may modulate tumor adaptations in fatty acid biosynthesis that promote survival of the transformed cells.
The aims of this research project on the role of SCD1 in hepatocellular carcinoma are to:
- Determine the contribution of monounsaturated fatty acid-induced noncanonical autophagy and the effect of SCD1 on hepatocellular carcinoma cell sensitivity to anti-cancer treatments or nutrient deprivation
- Perform preclinical studies using hepatocellular carcinoma patient-derived xenograft models and in vivo animal models to determine maximal anti-tumor benefit with SCD1 inhibition singly or in combination with other strategies
- Conduct a phase I clinical trial for SCD1-directed therapy in hepatocellular carcinoma