Targeting NAD Catabolism in Pancreatic Cancer Cells: Role of Small Molecule SIRT

靶向胰腺癌细胞中的 NAD 分解代谢：小分子 SIRT 的作用

基本信息

批准号：
8738912
负责人：
Eduardo N Chini
金额：
$ 30.76万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-18 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738912
关键词：
Affect Anabolism Animal Model Biopsy Cancer Cell Growth Cancer Etiology Catabolism Catalysis Cell Death Cell Survival Cells Cessation of life Clinic Clinical Research Clinical Trials Consumption Data Deacetylase Development Disease Dose Energy Metabolism Enzyme Activation Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Equilibrium Fatty Acids Human In Vitro Investigation KIAA1967 gene Lead Lysine Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolic Marker Metabolism Methods Neoplasm Metastasis Nicotinamide adenine dinucleotide Normal Cell Oxis Paclitaxel Pathway interactions Patients Pentoses Phase Phase I Clinical Trials Predisposition Process Proteins Publishing Reaction Role Seminal System Testing Therapeutic Tumor Tissue cancer cell caspase-3 cell growth chemotherapeutic agent cohort effective therapy gemcitabine in vivo neoplastic cell novel novel strategies outcome forecast pancreatic cancer cells pancreatic neoplasm pre-clinical preclinical study resistance mechanism response small molecule tumor

项目摘要

It has been known since the seminal discoveries of Otto Warburg in the early 1900¿s that cancer cells have unique metabolic features. However, it was not until recently that cancer cell metabolism became the focus of intense investigation. In particular, tumor cells undergo metabolic adaptations and have highly active glycolytic, pentose and fatty acid synthesis pathways. All of these metabolic changes contribute to increased tumor cell survival, proliferation and metastasis. Nicotinamide adenine dinucleotide (NAD) is central for these metabolic changes and cellular levels of NAD must be balanced to modulate these processes. A systematic analysis of the metabolism of NAD has not been performed in pancreatic cancer cells. NAD metabolism is regulated at the level of synthesis and degradation, and a decrease in cellular NAD levels leads to metabolic collapse and cell death. Recently, unique features of NAD metabolism have been described in cancer cells, opening the possibility that targeting NAD synthesis and/or degradation may lead to cancer specific metabolic collapse and serve as new therapy for a variety of human tumors including pancraeric cancer. Hence, we propose that activation of NAD degradation or inhibition of its synthesis will lead to a decrease in pancreatic cancer cell NAD levels and metabolic collapse, with subsequent tumor cell growth arrest and cell death. Our central hypothesis is that increasing NAD degradation (by activation of the enzyme SIRT1 with small molecules) or inhibiting its synthesis (using inhibitors of the enzyme Nampt) will cause metabolic collapse resulting in antitumor activity by itself and may also increase the antitumor activity of other chemotherapeutic agents. We will perform studies to elucidate the role of NAD metabolism in pancreatic cancer, characterize the major enzymes in pancreatic tumor tissue and test the combination of SRT3025 (a SIRT1 activator) with gemcitabine in a clinical trial of patients with metastatic pancreatic cancer. Our proposal is extremelly novel and of major relevance for the development of novel therapies for pancreatic cancer.

自 1900 年初 Otto Warburg 的开创性发现以来，它就广为人知。癌细胞有然而，直到最近，癌细胞的代谢才成为人们关注的焦点。特别是肿瘤细胞经历代谢适应并具有高度活跃性。所有这些代谢变化都会导致糖酵解、戊糖和脂肪酸合成途径的增加。细胞肿瘤的存活、增殖和转移是烟酰胺腺嘌呤二核苷酸（NAD）的核心。必须平衡代谢变化和 NAD 的细胞水平来调节这些过程。尚未对胰腺癌细胞中的 NAD 代谢进行分析。在合成和降解水平上受到调节，细胞 NAD 水平降低会导致代谢最近，NAD 代谢的独特特征已在癌细胞中得到描述。开启了靶向 NAD 合成和/或降解可能导致癌症特异性的可能性代谢崩溃并作为包括胰腺癌在内的多种人类肿瘤的新疗法。因此，我们认为激活NAD降解或抑制其合成将导致NAD的减少胰腺癌细胞 NAD 水平和代谢崩溃，随后肿瘤细胞生长停滞和细胞我们的中心假设是 NAD 降解增加（通过激活 SIRT1 酶）。小分子）或抑制其合成（使用Nampt酶抑制剂）会导致代谢塌陷本身导致抗肿瘤活性，也可能增加其他物质的抗肿瘤活性我们将进行研究以阐明 NAD 代谢在胰腺中的作用。癌症，表征胰腺肿瘤组织中的主要酶并测试 SRT3025（a SIRT1 激活剂）与吉西他滨在转移性胰腺癌患者的临床试验中。该提案非常新颖，对于胰腺新疗法的开发具有重要意义癌症。