Lipid Metabolism in Ethanol-Stimulated Liver Cancer

描述（由申请人提供）：肝细胞癌（HCC）是全球第五大常见癌症，占所有癌症相关死亡的三分之一。目前HCC的治疗选择包括手术切除、化疗和放射栓塞、移植和立体定向放射外科手术。唯一获批的晚期疾病药物干预包括索拉非尼（一种多酪氨酸激酶抑制剂）与多柔比星联合用药。然而，这种治疗方案只能延长几个月的无复发生存期。在大多数情况下，患者将在诊断后一年内死于这种疾病。这突出表明迫切需要确定HCC的新治疗靶点。相当多的证据支持从头脂肪生成（DNL）在HCC发展中的作用。然而，这一过程从未在肝癌中被体内靶向。在此，我们提出了两个具体的目标，将评估DNL在肝癌的发生和发展的作用。目的1将测试乙醇诱导的肿瘤发生和发展后，致癌物质治疗（二乙基亚硝胺）在一个新的线的转基因小鼠，缺乏肝脏表达的限速脂肪生成酶乙酰辅酶A羧化酶（ACC）1和2。目标2将评估饮食中的脂肪生成营养素与乙醇暴露相结合时如何促进HCC进展。在这个目标中，我们还将测试一种新的口服生物可利用的ACC抑制剂降低肿瘤负荷的功效。最低限度，该项目将确定ACC酶是否代表治疗HCC的药理学靶点，无论是否有乙醇刺激。最重要的是，我们将确定ACC酶作为新的药物靶点，可以在体内抑制ACC酶，以减少肝脏肿瘤负荷。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fifth most common cancer world-wide, contributing to one third of all cancer-related deaths. Current treatment options for HCC include surgical resection, chemo- and radioembolization, transplantation, and stereotactic radiosurgery. The only approved pharmacological interventions for advanced disease include Sorafenib, a multi-tyrosine kinase inhibitor, in combination with doxorubicin. However, this treatment regime only extends recurrence-free survival by several months. In most cases, patients will succumb to the disease within a year following diagnosis. This highlights an urgent need to identify new therapeutic targets in HCC. Considerable evidence supports a role for de novo lipogenesis (DNL) in HCC development. However, this process has never been targeted in vivo in liver cancer. Herein we propose two Specific Aims that will evaluate the role of DNL in HCC initiation and progression. Aim 1 will test ethanol-induced tumor initiation and progression following carcinogen treatment (diethylnitrosamine) in a novel line of transgenic mice that lack hepatic expression of the rate limiting lipogenic enzymes acetyl-CoA carboxylases (ACC) 1 and 2. Aim 2 will evaluate how lipogenic nutrients in the diet contribute to HCC progression when combined with ethanol exposure. In this Aim we will also test the efficacy of a novel orally bioavailable ACC inhibitor to reduce tumor burden. Minimally, this project will determine whether ACC enzymes represent a pharmacological target for the treatment of HCC both with and without an ethanol stimulus. Maximally, we will identify ACC enzymes as new drug targets that can be pharmacologically inhibited in vivo to reduce liver tumor burden.