Fatty Acid Synthase:Molecular Target for Breast Cancer Therapy & Chemoprevention

脂肪酸合成酶：乳腺癌治疗的分子靶点

• 批准号: 8295514
• 负责人: RUTH LUPU
• 金额: $ 46.12万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295514
• 关键词: Abbreviations; Acetyl Coenzyme A; Acetylcysteine; Address; Adipose tissue; Adjuvant; Apoptosis; Apoptotic; Biochemical Genetics; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; Cancer Patient; Carcinoma; Carnitine Palmitoyltransferase I; Cell Death; Cells; Cerulenin; Clinic; Clinical; Clinical Trials; Conduct Clinical Trials; Cysteine; Data; Development; Disease; Disease-Free Survival; Down-Regulation; ERBB2 gene; Effectiveness; Enzymes; Epidermal Growth Factor Receptor; Epigallocatechin Gallate; Esters; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen receptor positive; Event; Family member; Fatty Acids; Fatty-acid synthase; Figs - dietary; Fluorouracil; Foundations; Funding; Generations; Genes; Goals; Grant; Growth; Heregulin; Human; Immunohistochemistry; In Vitro; Laboratories; Lead; Link; Liver; MAPK14 gene; MAPK8 gene; Maintenance; Malonyl Coenzyme A; Mediating; Membrane Lipids; Membrane Potentials; Metabolic; Metastatic to; Mitochondria; Molecular; Molecular Target; NADP; National Surgical Adjuvant Breast and Bowel Project; Natural History; Neoadjuvant Therapy; Noninfiltrating Intraductal Carcinoma; Normal Cell; North Central Cancer Treatment Group; Noxae; Paclitaxel; Palmitates; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Play; Population; Production; Progesterone Receptors; Proliferating; Protein Family; Proteins; Publishing; Puma; Reactive Oxygen Species; Resistance; Risk; Role; Sphingolipids; Stress; Tamoxifen; Taxane Compound; Therapeutic; Tissues; Transcriptional Activation; Translating; Trastuzumab; Treatment Failure; Up-Regulation; Xenograft Model; base; cancer cell; cancer chemoprevention; cancer therapy; cell growth; chemotherapy; clinically relevant; cytochrome c; cytochrome c(3); cytotoxicity; design; effective therapy; gallocatechol; high risk; hormone therapy; in vivo; inhibitor/antagonist; inorganic phosphate; insight; long chain fatty acid; major outer membrane protein; malignant breast neoplasm; mitochondrial membrane; novel; novel therapeutics; outcome forecast; overexpression; preclinical study; prevent; research study; response; response marker; sphingosine 1-phosphate; taxane; theranostics; therapeutic target; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): Fatty Acid Synthase (FASN) is an enzyme that catalyzes the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA in cells. Normal cells (except liver and adipose tissue) have low levels of FASN activity. In rapidly proliferating cancer cells fatty acids can be synthesized de novo to provide lipids for membrane formation. Our general hypothesis is that FASN is a promising therapeutic target for invasive breast carcinomas. FASN is highly expressed in invasive breast and other carcinomas, and is prominent in higher grade tumors correlating with poor prognosis. Our data shows that 60% of invasive breast carcinomas express high levels of FASN and FASN expression is a marker for poor prognosis and poor disease free survival. Interestingly, FASN is highly coexpressed with the three breast cancer histopathological groups: Estrogen Receptor positive (ER+), HER2 3+ overexpressing (HER2+) and triple negative (TN) [which do not express ER, Progesterone Receptor (PgR), and HER2+). Our preliminary studies show that pharmacological inhibition of FASN in breast cancer synergizes with chemotherapeutical agents such as Taxol, and with antiestrogens and trastuzumab targeted therapies increasing growth inhibition and apoptotic cell death in vitro and in vivo. We demonstrated that blockage of FASN inhibits tumor growth and induces apoptosis, triggering deteriorating effects which lead to apoptotic cell death including: i inhibition of palmitate, hence the inhibition of sphingolipids synthesis; ii) mitochondria damage and release of Cyt c; iii) increase Reactive Oxygen Species (ROS) generation; and iv) upregulation of BH3-only family proteins (Noxa, Bim, Puma). In this proposal we will extend these concepts using a variety of biochemical, genetic and therapeutic approaches: First, we will examine the clinical value of FASN as a theranostic (predictive) marker for response to targeted therapy in breast-cancer patients, in adjuvant and neoadjuvant setting. Second, we will assess the role of: i) BH3-only proteins Noxa, Bim and Puma in FASN inhibition induced apoptosis: ii) the synergistic effect of inhibitors of FASN and Taxol induced apoptosis; iii) the lnk between FASN inhibition and increased ROS production and BH3-only protein upregulation. Last, we will perform preclinical studies to assess a newly develop anti-FASN agent in combination with antiestrogens, Trastuzumab and Taxol. This proposal will provide new insight into the action of FASN inhibitors and the information needed to translate our findings into the clinic. Our goal is to develop novel rationally designed therapeutic approaches for breast cancer. PUBLIC HEALTH RELEVANCE: This application responds to the urgent need to develop strategies to predict response to cancer treatments. The characterization of Fatty Acid Synthase as a molecular event accompanying the pathogenesis and natural history of breast cancer disease will help determine its clinical relevance to metastatic breast cancer patients and will help in the development of effective treatment strategies.

描述（由申请方提供）：脂肪酸合酶（Fatty Acid Synthase）是一种在细胞中催化乙酰辅酶A和丙二酰辅酶A从头合成长链脂肪酸的酶。正常细胞（除了肝脏和脂肪组织）具有低水平的Festival活性。在快速增殖的癌细胞中，脂肪酸可以从头合成，以提供用于膜形成的脂质。我们的一般假设是，FRESINS是浸润性乳腺癌的一个有前途的治疗靶点。FXR在浸润性乳腺癌和其他癌症中高度表达，并且在与不良预后相关的较高级别肿瘤中突出。我们的数据显示，60%的浸润性乳腺癌表达高水平的FXR，并且FXR表达是预后不良和无病生存不良的标志物。有趣的是，FXR与三种乳腺癌组织病理学组高度共表达：雌激素受体阳性（ER+）、HER 2 3+过表达（HER 2+）和三阴性（TN）[其不表达ER、孕酮受体（PgR）和HER 2 +]。我们的初步研究表明，药理学抑制乳腺癌中的FGFAP与化疗药物如紫杉醇，抗雌激素和曲妥珠单抗靶向治疗协同作用，在体外和体内增加生长抑制和凋亡细胞死亡。我们证明了阻断FXR抑制肿瘤生长并诱导凋亡，触发导致凋亡性细胞死亡的恶化作用，包括：i抑制棕榈酸酯，因此抑制鞘脂合成; ii）线粒体损伤和Cyt c释放; iii）增加活性氧（ROS）产生;以及iv）上调仅BH 3家族蛋白（Noxa、Bim、Puma）。在本提案中，我们将使用各种生物化学，遗传学和治疗方法扩展这些概念：首先，我们将研究Festival作为辅助和新辅助治疗乳腺癌患者靶向治疗反应的治疗诊断（预测）标志物的临床价值。第二，我们将评估：i）仅BH 3蛋白Noxa、Bim和Puma在FXR抑制诱导的细胞凋亡中的作用; ii）FXR和紫杉醇抑制剂诱导的细胞凋亡的协同作用; iii）FXR抑制和增加的ROS产生和仅BH 3蛋白上调之间的关系。最后，我们将进行临床前研究，以评估一种新开发的抗雌激素药物，曲妥珠单抗和紫杉醇的组合。该提案将为Festival抑制剂的作用提供新的见解，并将我们的发现转化为临床所需的信息。我们的目标是为乳腺癌开发新的合理设计的治疗方法。 公共卫生相关性：该应用程序响应了开发预测癌症治疗反应的策略的迫切需求。将脂肪酸合成酶表征为伴随乳腺癌疾病发病机制和自然史的分子事件，将有助于确定其与转移性乳腺癌患者的临床相关性，并有助于制定有效的治疗策略。