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

• 批准号: 9331427
• 负责人: Eduardo N Chini
• 金额: $ 28.91万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9331427
• 关键词: Affect; Anabolism; Animal Model; Biopsy; CASP3 gene; 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; Enzymes; 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; Paclitaxel; Pathway interactions; Patients; Pentoses; Pharmacology; Phase; Predisposition; Process; Proteins; Publishing; Reaction; Role; SIRT1 gene; Seminal; Sirtuins; System; Testing; Therapeutic; Tumor Tissue; cancer cell; cell growth; chemotherapeutic agent; cohort; effective therapy; gemcitabine; in vivo; neoplastic cell; novel; novel strategies; novel therapeutics; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; phase I trial; pre-clinical; preclinical study; resistance mechanism; response; small molecule; targeted treatment; tumor; tumor metabolism

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 Otto Warburg 的开创性发现以来，人们就知道癌细胞具有 独特的代谢特征。然而直到最近，癌细胞的代谢才成为人们关注的焦点 的深入调查。特别是肿瘤细胞经历代谢适应并具有高度活跃的 糖酵解、戊糖和脂肪酸合成途径。所有这些代谢变化都有助于增加 肿瘤细胞的存活、增殖和转移。烟酰胺腺嘌呤二核苷酸（NAD）是这些的核心 必须平衡代谢变化和 NAD 的细胞水平来调节这些过程。一个系统的 尚未在胰腺癌细胞中进行 NAD 代谢分析。 NAD代谢是 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 崩溃和细胞死亡。最近，NAD 代谢的独特特征在癌细胞中得到了描述， 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 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 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 化疗剂。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（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 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。