# Project 3: Inhibition of SCD1 as a therapeutic strategy for HCC

> **NIH NIH P50** · MAYO CLINIC ROCHESTER · 2022 · $358,289

## Abstract

PROJECT 3 – PROJECT SUMMARY
Understanding metabolic adaptations in hepatocellular cancer (HCC) that impart survival benefits may provide
new treatment approaches for these highly chemoresistant cancers. Recent studies have implicated lipid
biosynthesis and desaturation as a requirement for HCC survival. Stearoyl CoA desaturase (SCD1) is a key
mediator of FA biosynthesis, and rate-limiting in conversion of saturated fatty acids (SFA) such as palmitic acid
to monounsaturated fatty acids (MUFA) such as palmitoleic acid. Although SFA have been implicated in
lipotoxicity, MUFA can induce non-canonical autophagy, activate Wnt signaling, enhance membrane turnover,
and increase energy production. Thus, SCD-1 can contribute to tumor cell survival through metabolic
adaptations resulting from enhanced conversion of SFA to MUFA. We hypothesize that targeting SCD1 may
prove therapeutically beneficial to HCC patients by modulating tumor adaptations in fatty acid biosynthesis that
promote survival of transformed cells. Using a combined computational and synthetic chemistry approach, we
have developed novel highly efficacious SCD1 inhibitors. Amongst these, our lead SCD1 inhibitor (SSI-4) dose
dependently inhibits cell proliferation in HCC cell lines (1 - 3 nM IC50), demonstrates synergy with sorafenib,
has excellent oral bioavailability, is well tolerated with long-term daily dosing and possesses single agent
antitumor activity in a HCC patient derived xenograft (PDX) mouse model. In Aim 1, we will identify the role of
SCD-1 dependent non-canonical autophagic pathways in mediating therapeutic resistance. The contribution of
MUFA induced non-canonical autophagy and the effect of SCD1 inhibition on HCC cell sensitivity to anticancer
treatments or nutrient deprivation will be determined. In Aim 2 we will perform preclinical studies using HCC
PDX models and in vivo mouse models to determine maximal antitumor benefit with SCD1 inhibition singly or
in combination with other strategies. In Aim 3, we will optimize patient selection and perform a Phase 1 clinical
trial for SCD1 directed therapy in HCC.

## Key facts

- **NIH application ID:** 10468831
- **Project number:** 5P50CA210964-05
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** STEVEN R ALBERTS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $358,289
- **Award type:** 5
- **Project period:** 2018-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468831

## Citation

> US National Institutes of Health, RePORTER application 10468831, Project 3: Inhibition of SCD1 as a therapeutic strategy for HCC (5P50CA210964-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468831. Licensed CC0.

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