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：癌细胞代谢由许多异常调节的代谢组成途径包括脂质合成（脂肪生成）、糖酵解（瓦伯格效应），而前列腺癌。 PCa）细胞不会表现出葡萄糖摄取升高（这是瓦尔堡效应的一个特征），但它们确实表现出葡萄糖摄取升高其特点是糖酵解和脂肪生成酶表达升高，而正常细胞也获得脂质。 PCa 细胞主要依赖于外源脂质合成，重要的是，脂质合成水平升高。糖酵解和脂肪生成酶的表达驱动核苷酸、蛋白质和代谢物的产生脂质产生，促进细胞增殖、能量产生、细胞内信号传导和免疫重要的是，已经确定了脂肪生成和异常糖酵解酶表达，如 PCa 病因和侵袭性的真正介质，因此有针对性地破坏这些途径是一种潜在的 PCa 治疗方法，目前已开发出多种抑制剂来靶向治疗。不幸的是，这些抑制剂的功效较差并且具有相关的毒副作用。结果是，在啮齿动物癌症模型中出现了严重的体重减轻和厌食症。目前临床上尚无针对致癌代谢的 PCa 治疗方法。专注于阻断雄激素受体活性和细胞分裂的治疗方法尚未能够显着延长患者的寿命，这是由于 PCa 细胞能够适应并持续生长。通过“重新布线”雄激素受体信号传导并绕过目标细胞侵入其他组织转移性、去势抵抗性前列腺癌是导致所有前列腺癌死亡的原因。目标是开发一种有效、安全且能够替代的癌症代谢抑制剂我们探索了转录抑制。肝脏 X 受体 (LXR) 的活性；多重糖酵解表达的主要调节因子脂肪生成基因可能是抑制癌症代谢的有效手段。 LXR 反向激动剂：抑制 LXR 转录活性的 SR9243 显着阻断。 Warburg 效应和脂肪生成，能够破坏 PCa 细胞生长而不产生体重减轻或其他不良副作用，以研究使用 SR9243 的 LXR 反向激动是否有用。对于 PCa 的治疗方法，我们将解决 2 个具体目标，具体目标 1 将测试疗效。 SR9243 在 PCa 原发性肿瘤模型和特定转移模型中对抗 PCa 肿瘤。目标 2 将研究 SR9243 是否能够增强目前使用的 PCa 治疗的疗效当与患者衍生的 PCa 异种移植模型联合使用时，该研究应生成。一种治疗 PCa 的新方法，将为未来旨在探索 PCa 的项目奠定基础 LXR转录活性在PCa代谢中的机制作用。