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

项目 3：抑制 SCD1 作为 HCC 的治疗策略

基本信息

批准号：
10006084
负责人：
STEVEN R ALBERTS
金额：
$ 33.17万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006084
关键词：
Apoptosis Apoptotic Autophagocytosis BAY 54-9085 Biological Availability Biological Markers Brain Hypoxia-Ischemia Cancer Patient Cancer cell line Cell Death Cell Proliferation Cell Survival Clinic Clinical Data Data Set Dose Funding Gene Proteins Genomics Golgi Apparatus Grant Hepatobiliary Hypoxia Investigation Lead Lipids Malignant Neoplasms Maximum Tolerated Dose Mediating Mediator of activation protein Membrane Metabolic Monounsaturated Fatty Acids Nutrient Oral Palmitic Acids Pathway interactions Patient Selection Patients Phase I Clinical Trials Primary carcinoma of the liver cells Principal Investigator Production Proteins Reporting Resistance Role Sampling Saturated Fatty Acids Small Business Technology Transfer Research Small Interfering RNA Stearoyl-CoA Desaturase Synthesis Chemistry Therapeutic Therapeutic Agents Tissues Toxicokinetics Translational Research Treatment Efficacy WNT Signaling Pathway Xenograft Model Xenograft procedure anticancer treatment antitumor agent antitumor effect base biobank cancer cell cancer survival cancer therapy cell transformation clinical practice combat computational chemistry early phase clinical trial effective therapy endoplasmic reticulum stress fatty acid biosynthesis in vivo inhibitor/antagonist lipid biosynthesis mouse model neoplastic cell novel novel marker nutrient deprivation palmitoleic acid phase 1 study phase I trial potential biomarker pre-clinical preclinical study predictive marker response biomarker small molecule synergism targeted treatment therapeutic target therapy resistant tumor tumor growth

项目摘要

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.

项目3 -项目总结