Lipogenic inhibitors in prevention of oncogene induced liver cancer

描述（由申请人提供）：肝细胞癌（HCC）是世界范围内癌症死亡的主要原因之一。HCC具有明确的危险因素：慢性HBV或HCV感染占所有HCC病例的85%以上。如此明确的人群使HCC成为化学预防的理想恶性肿瘤类型。最近，我们通过在小鼠中过表达c-Myc或同时表达活化形式的AKT和Ras （AKT/Ras）建立了新的小鼠HCC模型。我们发现c-Myc和AKT/Ras诱导的hcc均表现出脂肪生成增加。然而，详细的脂质谱分析显示，AKT/Ras诱导的HCC具有高水平的甘油三酯和中度升高的胆固醇，而c-Myc诱导的HCC具有极高的胆固醇水平，但甘油三酯水平轻度升高。基于这些初步结果，我们假设不同的癌基因在肝癌发生过程中诱导不同的脂质代谢途径；针对不同脂肪生成途径的药物可能在特定癌基因诱导的肝脏肿瘤中显示出截然不同的化学预防活性。这一假设将在两个方面得到检验。在Aim One中，我们将确定脂质途径抑制剂包括C-75 （FASN抑制剂）、辛伐他汀（MHGCR抑制剂）和脂肪抑制素（SREBP1/2抑制剂）在c-Myc诱导的小鼠HCC中的化学预防活性。在第二阶段，我们将确定脂肪生成途径抑制剂在AKT/Ras诱导的小鼠HCC中的化学预防活性。总之，该研究将研究针对不同致癌基因背景下不同的脂肪生成途径成分的脂肪生成途径抑制剂的化学预防潜力。它代表了一个具有明确研究目标和范围的创新试点项目。该研究将对脂质代谢在肝癌发生过程中的作用提供新的见解，并为预防这种恶性肿瘤提供新的策略。

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death world-wide. HCC has well characterized risk factors: chronic HBV or HCV infection accounts for over 85% of all HCC cases. Such well- defined population makes HCC an ideal type of malignancy for chemoprevention. Recently, we established novel murine HCC models by overexpressing c-Myc or concomitant expressing activated forms of AKT and Ras (AKT/Ras) in mice. We found that HCCs induced by c-Myc as well as AKT/Ras both demonstrated increased lipogenesis. However, detailed lipid profiling analysis showed that while HCC induced by AKT/Ras has high levels of triglyceride and moderately elevated cholesterol, HCC induced by c-Myc shows extremely high levels of cholesterol, but mild increase in triglyceride levels. Based on these preliminary results, we hypothesize that different oncogenes induce distinct lipid metabolic pathways during hepatic carcinogenesis; and drugs that target distinct lipogenic pathways may show drastically different chemoprevention activities in liver tumors induced by specific oncogenes. The hypothesis will be tested in two aims. In Aim One, we will determine the chemoprevention activity of lipogenic pathway inhibitors including C-75 (FASN inhibitor), simvastatin (MHGCR inhibitor) and Fatostatin (SREBP1/2 inhibitor) in c-Myc induced mouse HCC. In Aim Two, we will determine the chemoprevention activity of lipogenic pathway inhibitors in AKT/Ras induced mouse HCC. Altogether, the proposed study will examine the chemoprevention potential of lipogenic pathway inhibitors that target distinct lipogenic pathway components in the context of different oncogenes. It represents an innovative pilot project with defined research goal and scope. The study will provide novel insight into the role of lipid metabolism during hepatic carcinogenesis, and provide novel strategy for the prevention of this malignancy.