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年代初期奥托·沃堡（Otto Warburg）第二次发现以来，癌细胞已知独特的代谢特征。但是，直到最近，癌细胞代谢才成为重点激烈的调查。特别是，肿瘤细胞进行代谢适应，具有高度活跃糖酵解，戊糖和脂肪酸合成途径。所有这些代谢变化都会增加肿瘤细胞存活，增殖和转移。烟酰胺腺苷二核苷酸（NAD）是其中的中心必须平衡NAD的代谢变化和细胞水平以调节这些过程。系统 NAD代谢的分析尚未在胰腺癌细胞中进行。 NAD代谢是在合成和降解水平下调节，细胞NAD水平的降低导致代谢崩溃和细胞死亡。最近，在癌细胞中描述了NAD代谢的独特特征，打开靶向NAD合成和/或降解的可能性可能导致特定于癌症代谢崩溃，并作为包括胰腺癌在内的多种人类肿瘤的新疗法。因此，我们提出，NAD降解或抑制其合成的激活将导致减少胰腺癌细胞NAD水平和代谢崩溃，随后肿瘤细胞生长停滞和细胞死亡。我们的中心假设是增加NAD降解（通过激活酶SIRT1 小分子）或抑制其合成（使用酶NAMPT的抑制剂）会导致代谢崩溃，导致抗肿瘤活性本身，也可能增加其他的抗肿瘤活性化学治疗剂。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的组合（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。我们的提案是极端的小说，与开发胰腺新疗法的主要意义癌症。