Treating prostate cancer by pharmacological coinhibition of the Warburg effect and lipogenesis

通过药理学共同抑制 Warburg 效应和脂肪生成来治疗前列腺癌

基本信息

批准号：
9392247
负责人：
Colin ASHTON Flaveny
金额：
$ 19.77万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9392247
关键词：
Acetates Address Adverse effects Agonist Androgen Receptor Androgens Anorexia Apoptotic Biological Assay Body Weight decreased Bypass Cancer Etiology Cancer Model Cell Death Cell Proliferation Cell division Cessation of life Characteristics Chemotherapy-Oncologic Procedure Chimeric Proteins Cholesterol Homeostasis Clinic Clinical Clinical Treatment Clinical Trials Consequentialism Disease Outcome Dose Effectiveness Elements Enzyme Inhibitor Drugs Enzymes Etiology Exhibits FABP4 gene FASN gene Foundations Future Genes Genetic Transcription Glycolysis Growth Human Immune Evasion Incidence Invaded Investigation LXRalpha protein Ligands Link Lipids Liver X Receptor Longevity Malignant - descriptor Malignant neoplasm of prostate Mediator of activation protein Metabolic Metabolic Pathway Metabolism Metastatic Prostate Cancer Microtubules Modeling Neoplasm Metastasis Normal Cell Nucleotides Oncogenic PC3 cell line Pathway interactions Patients Pharmaceutical Preparations Primary Neoplasm Production Prostate Prostatic Proteins Receptor Inhibition Receptor Signaling Recruitment Activity Refractory Regulation Resistance Rodent Role Signal Transduction Source Tissues Transactivation Tumor Burden Warburg Effect Xenograft Model Xenograft procedure abiraterone aerobic glycolysis cancer invasiveness cancer pharmacology cancer therapy castration resistant prostate cancer cell growth cellular targeting chemotherapy design efficacy testing glucose uptake in vivo in vivo Model inhibitor/antagonist lipid biosynthesis nanoluciferase neoplastic cell novel overexpression pre-clinical promoter prostate cancer cell prostate cancer model success taxane tumor tumor growth tumor metabolism tumor progression tumor xenograft

项目摘要

Project Summary: Cancer cell metabolism comprises of a number of aberrantly regulated metabolic pathways including lipid synthesis (lipogenesis), glycolysis (the Warburg Effect). While prostate cancer PCa) cells do not exhibit elevated glucose uptake, a characteristic of the Warburg effect, they do feature elevated glycolysis and lipogenesis enzyme expression. Also whereas normal cells obtain lipids primarily from exogenous sources PCa cells depend on de novo lipid synthesis. Importantly, elevated glycolysis and lipogenesis enzyme expression drive metabolite production for nucleotide, protein and lipid production, which facilitate cell proliferation, energy production, intracellular signaling and immune evasion. Importantly lipogenesis and aberrant glycolysis enzyme expression have been identified, as bona-fide mediators of PCa etiology and invasiveness, therefore targeted disruption of these pathways are a potential treatment approach for PCa. A number of inhibitors have been developed to target cancer metabolism. Unfortunately these inhibitors have poor efficacy and have associated toxic side effects including severe weight-loss and anorexia in rodent cancer models. As a result there are currently no treatments for PCa that target oncogenic metabolism currently used in the clinic. PCa treatments that focus on blocking androgen receptor activity and cell division have not been able to extend patient lifespan substantially. This is due to PCa cells adapting and continuing to grow and invade other tissues by “rewiring” androgen receptor signaling and bypassing targeted cellular pathways. Metastatic, castration resistant PCa is responsible for all PCa deaths. Therefore our objective is to develop a cancer metabolism inhibitor that is effective, safe and will be able to replace, supplement or enhance current treatments. We hypothesized that suppression of the transcriptional activity of the liver-X-receptor (LXR); a master regulator of expression of multiple glycolysis and lipogenesis genes could be a potent means of inhibiting cancer metabolism. Therefore we designed a LXR inverse agonist: SR9243 that suppresses LXR transcriptional activity. SR9243 significantly blocks the Warburg effect and lipogenesis and is able to disrupt PCa cell growth without producing weight loss or other undesired side effects. To investigate whether LXR inverse agonism, using SR9243, is a useful treatment approach for PCa we will address 2 specific aims. Specific Aim 1 will test the efficacy of SR9243 against PCa tumors in a PCa orthotopic primary tumor model and a metastatic model. Specific Aim 2 will investigate whether SR9243 is able to enhance the efficacy of currently used PCa treatments when used in combination using a patient derived xenograft model of PCa. This study should generate a novel treatment approach for PCa and will lay the foundation for future projects aimed at exploring the mechanistic role of LXR transcriptional activity in PCa metabolism.

项目摘要：癌细胞代谢包括许多异常调节的代谢包括脂质合成（脂肪生成），糖酵解（Warburg效应）在内的途径。而前列腺癌 PCA）细胞没有表现出升高的葡萄糖吸收，这是Warburg效应的特征特征升高的糖酵解和脂肪生成酶表达。同样，正常细胞获得脂质首先来自外源性来源PCA细胞依赖于从头脂质合成。重要的是，高架糖酵解和脂肪生成酶表达驱动核苷酸，蛋白质和脂质产生，这些产生能够促进细胞增殖，能量产生，细胞内信号传导和免疫逃避。重要的是，脂肪生成和异常糖酵解酶表达已被鉴定为 PCA病因和侵入性的真正的介质，因此针对这些途径的破坏是PCA的潜在治疗方法。已经开发了许多抑制剂来靶向癌症代谢。不幸的是，这些抑制剂的效率较差，并且有毒一面在啮齿动物癌模型中包括严重减肥和厌食的影响。结果有目前尚无针对诊所目前使用的致癌代谢的PCA治疗方法。 PCA 专注于阻断雄激素受体活性和细胞分裂的治疗方法无法大大延长患者的寿命。这是由于PCA细胞适应并继续增长，并且通过“重新布线”雄激素受体信号传导和绕过目标细胞来入侵其他组织途径。转移性，抑制PCA均导致所有PCA死亡。因此我们的目的是开发一种有效，安全并且能够取代的癌症代谢抑制剂补充或增强当前治疗。我们假设抑制转录肝脏-X受体（LXR）的活性；多种糖酵解和表达的主调节剂脂肪生成基因可能是抑制癌症代谢的潜在手段。因此，我们设计了 LXR反向激动剂：SR9243抑制LXR转录活性。 SR9243显着阻碍 Warburg效应和脂肪形成，能够破坏PCA细胞的生长而不会产生体重减轻或其他不需要的副作用。研究使用SR9243的LXR是否反向激动剂是一个有用的 PCA的治疗方法我们将解决2个具体目标。特定目标1将测试在PCA原位原发性肿瘤模型和转移模型中，针对PCA肿瘤的SR9243。具体的 AIM 2将调查SR9243是否能够提高当前使用的PCA处理的效率当使用患者衍生的PCA衍生Xenographic模型组合使用时。这项研究应该产生 PCA的一种新型治疗方法，将为未来的项目奠定基础，以探索 LXR转录活性在PCA代谢中的机械作用。