Project 3: Inhibition of SCD1 As a Therapeutic Strategy for Hepatocellular Carcinoma

Lay summary

Sugars are thought of as the source of energy to keep cancer cells alive. Cancers such as liver cancer also can depend on fatty acids as a source to make more energy. Our research team developed a new compound called SSI-4 (aka MTI-301) that can be taken by mouth to stop liver cancer cells from making fatty acids. The liver cells die when given SSI-4. We also combined SSI-4 with other drugs approved for liver cancer, such as regorafenib, to kill even more cancer cells. We envision a clinical trial using these two drugs together to ultimately cure patients with liver cancer or provide a longer life with better quality of living.

Scientific rationale

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, investigators in this project 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.

We're 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. We're also seeking predictive biomarkers of response that could be clinically useful.

Hypothesis

We hypothesize that targeting the stearoyl CoA desaturase 1 (SCD1) may modulate tumor adaptations in fatty acid biosynthesis that promote survival of the transformed cells.

Project aims

The aims of this project 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 1 clinical trial for SCD1-directed therapy in hepatocellular carcinoma