Lipid Metabolism in Liver Cancer

肝癌中的脂质代谢

• 批准号: 10277183
• 负责人: Bingning Dong
• 金额: $ 36.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277183
• 关键词: Affect; Agonist; Antihistamines; CAR receptor; CD36 gene; Cancer Etiology; Cessation of life; Clinical Trials; Combined Modality Therapy; Development; Diet; Effectiveness; Essential Fatty Acids; FDA approved; Fatty Acids; Gene Expression; Genetic Suppression; Genetic Transcription; Goals; Grant; Growth; High Fat Diet; Human; Incidence; Knock-out; Link; Lipids; Malignant Epithelial Cell; Malignant neoplasm of liver; Mediating; Metabolic syndrome; Molecular; Mus; Nuclear Receptors; Obesity; Pharmaceutical Preparations; Pharmacology; Primary carcinoma of the liver cells; Repression; Risk Factors; Role; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Xenograft procedure; deprivation; epidemiology study; feeding; gene synthesis; in vivo; inhibitor/antagonist; lipid biosynthesis; lipid metabolism; liver cell proliferation; modifiable risk; neutralizing antibody; non-alcoholic fatty liver disease; novel therapeutic intervention; overexpression; programs; therapeutic target; therapeutically effective; tumor; tumorigenesis; uptake

Project Summary Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide, with 5- year survival less than 12%. Paralleling the increased incidence of HCC is the rise of obesity and the related metabolic syndrome including nonalcoholic fatty liver disease (NAFLD), and recent epidemiologic studies directly link NAFLD to HCC. The identification of obesity as a major modifiable risk factor for HCC development highlights the urgency of understanding the underlying mechanisms that drive the linkage of NAFLD and HCC. Our long-term goal is to understand the molecular mechanism underlying obesity related HCC and develop novel therapeutic strategies. The overall objective for this grant is to investigate how nuclear receptor CAR regulates HCC lipid synthesis to promote tumorigenesis and determine whether simultaneously blocking CAR and lipid uptake is effective in obesity related HCC. Our preliminary results demonstrate that suppressing CAR activity via Inverse Agonist (CAR-IA) inhibits mouse HCC growth with normal chow diet, however this tumor inhibition effect can be completely reversed by high fat diet (HFD) feeding. Mechanistically, we found that CAR suppression by CAR-IA inhibits tumor lipid synthesis in both mouse and human HCC. CD36 mediated lipid uptake potentially reverse lipid deprivation condition and growth inhibition caused by CAR-IA in HCC from HFD feeding. These exciting results support our hypothesis that (1) suppressing CAR inhibits normal chow HCC growth through repressing tumor lipid synthesis and (2) blockade of both CAR mediated de novo lipid synthesis and CD36 mediated exogenous lipid uptake will provide synthetic lethality in obesity associated HCC. In Aim 1, we will define the mechanisms by which CAR inhibition represses HCC lipid synthesis and growth. Aim 2 will determine whether lipid uptake blockade sensitizes mouse HCC/HFD to CAR inhibition. Lastly, Aim 3 will define the impact of CAR suppression on normal and obesity related human HCC. Targeting tumor lipid synthesis has opened a promising therapeutic window for many tumors, including HCC. However, strong toxic effects and limited effectiveness of the current lipogenic inhibitors have confounded clinical trials. In contrast, CAR suppression by mouse CAR-IA shows no toxicity in mice and human CAR-IA meclizine is an FDA proved antihistamine drug. Importantly, this proposal integrates the overlapping roles of lipid synthesis and uptake in obesity related HCC. Successful deployment of co-treatment with inhibitors for lipid synthesis and uptake would have a major impact on obesity related HCC.

项目摘要 肝细胞癌（HCC）是全球与癌症相关死亡的第二大最常见原因，有5-- 年生存不到12％。肥胖症的兴起和相关的HCC的发生率增加是 代谢综合征包括非酒精性脂肪肝病（NAFLD）和最近的流行病学研究 直接将NAFLD链接到HCC。将肥胖症鉴定为HCC开发的主要可修改风险因素 突出了理解推动NAFLD和HCC链接的基本机制的紧迫性。 我们的长期目标是了解与肥胖相关的HCC的分子机制并发展 新颖的治疗策略。该赠款的总体目标是研究核受体汽车如何 调节HCC脂质合成以促进肿瘤发生并确定是否同时阻止CAR 脂质摄取在与肥胖相关的HCC中有效。我们的初步结果表明抑制汽车 通过反向激动剂（CAR-IA）的活性可抑制小鼠HCC的生长，但这种肿瘤 高脂饮食（HFD）喂养可以完全逆转抑制作用。从机械上讲，我们发现那辆车 CAR-IA抑制抑制小鼠和人HCC中的肿瘤脂质合成。 CD36介导的脂质 摄取可能反向脂质剥夺条件和HFD中HCC中的CAR-IA引起的增长抑制作用 进食。这些令人振奋 通过抑制肿瘤脂质合成和（2）两种媒介物介导的从头脂质的增长 合成和CD36介导的外源脂质摄取将在肥胖相关的HCC中提供合成的致死性。 在AIM 1中，我们将定义CAR抑制抑制HCC脂质合成和生长的机制。 AIM 2将确定脂质摄取阻滞是否使小鼠HCC/HFD对CAR抑制敏感。最后，目标 3将定义抑制汽车对正常和肥胖相关的人类HCC的影响。靶向肿瘤脂质 合成为包括HCC在内的许多肿瘤打开了一个有希望的治疗窗口。但是，有毒 当前脂肪生成抑制剂的影响和有限的有效性使临床试验混淆。相比之下， 小鼠CAR-IA抑制汽车在小鼠中没有毒性，而人类Car-ia Meclizine已证明是FDA 抗组胺药。重要的是，该提案整合了脂质合成和吸收的重叠作用 与肥胖有关的HCC。成功部署与脂质合成和摄取的抑制剂共同治疗 将对与肥胖有关的HCC产生重大影响。