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

项目3 -项目概要 了解肝细胞癌（HCC）中赋予生存益处的代谢适应可能提供 这些高度耐药癌症的新治疗方法。最近的研究表明， 生物合成和去饱和是HCC存活的必要条件。硬脂酰辅酶A去饱和酶（SCD 1）是一个关键 FA生物合成的介体，以及饱和脂肪酸（SFA）如棕榈酸转化的限速作用 单不饱和脂肪酸（MUFA），如棕榈油酸。尽管SFA与 在脂毒性方面，MUFA可以诱导非典型的自噬，激活Wnt信号传导，增强膜更新， 并增加能源生产。因此，SCD-1可以通过代谢途径促进肿瘤细胞存活。 由于SFA向MUFA的转化增强而产生的适应。我们假设针对SCD 1可能 通过调节脂肪酸生物合成中的肿瘤适应性， 促进转化细胞的存活。使用结合计算和合成化学方法，我们 已经开发出新型高效的SCD 1抑制剂。其中，我们的主要SCD 1抑制剂（SSI-4）剂量 依赖性抑制HCC细胞系中的细胞增殖（1 - 3 nM IC 50），显示与索拉非尼的协同作用， 具有优良的口服生物利用度，长期每日给药耐受性良好， 在HCC患者来源的异种移植物（PDX）小鼠模型中的抗肿瘤活性。在目标1中，我们将确定 SCD-1依赖性非经典自噬途径介导治疗抗性。的贡献 MUFA诱导的非典型自噬及抑制SCD 1对肝癌细胞抗癌敏感性的影响 将确定治疗或营养剥夺。在目标2中，我们将使用HCC进行临床前研究 PDX模型和体内小鼠模型，以确定单独或 结合其他战略。在目标3中，我们将优化患者选择并进行1期临床试验， 在HCC中进行SCD 1导向治疗的试验。

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.