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

项目3--项目总结 了解肝细胞癌(HCC)的代谢适应对生存的好处可能提供 这些高度耐药癌症的新治疗方法。最近的研究表明，脂质与 生物合成和去饱和度是肝细胞癌存活的必要条件。硬脂酰辅酶A去饱和酶(SCD1)是一个关键 脂肪酸生物合成的介体和棕榈酸等饱和脂肪酸转化的限速 到单不饱和脂肪酸(MUFA)，如棕榈油酸。尽管SFA被牵连到 脂毒性，MUFA可以诱导非典型自噬，激活Wnt信号，提高膜周转， 并增加能源生产。因此，SCD-1可以通过代谢促进肿瘤细胞的存活 加强将SFA转换为MUFA所产生的适应。我们假设以SCD1为靶点可能 通过调节脂肪酸生物合成中的肿瘤适应，证明对肝癌患者的治疗有益 促进转化细胞的存活。使用计算和合成化学相结合的方法，我们 已经开发出新型高效的SCD1抑制剂。其中，我们的主要SCD1抑制剂(SSI-4)剂量 依赖地抑制肝癌细胞系(1-3 nM IC50)的细胞增殖，显示与索拉非尼的协同作用， 具有极好的口服生物利用度，长期每日给药耐受性好，并具有单一药物 肝癌患者来源的异种移植(Pdx)小鼠模型的抗肿瘤活性。在目标1中，我们将确定 SCD-1依赖的非典型自噬通路在介导治疗耐药中的作用。的贡献 多不饱和脂肪酸诱导的非典型自噬及抑制SCD1对肝癌细胞抗癌敏感性的影响 治疗或营养剥夺将被确定。在目标2中，我们将使用肝细胞癌进行临床前研究 PDX模型和体内小鼠模型确定单一或联合抑制SCD1的最大抗肿瘤益处 与其他战略相结合。在目标3中，我们将优化患者选择并执行第一阶段临床 SCD1在肝癌中的定向治疗试验。

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.