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

自从1900年初�S的奥托·沃堡的开创性发现以来，人们就知道癌细胞具有 独特的新陈代谢特征。然而，直到最近，癌细胞代谢才成为人们关注的焦点。 严密调查的结果。特别是，肿瘤细胞经历新陈代谢适应并具有高度的活性 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)是这些疾病的中心 NAD的代谢变化和细胞水平必须保持平衡，才能调节这些过程。一个系统的 尚未对NAD在胰腺癌细胞中的代谢进行分析。NAD新陈代谢是 在合成和降解水平上进行调节，细胞NAD水平的下降导致代谢 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/或降解可能导致癌症特异性的可能性 新陈代谢崩溃，并作为包括泛癌在内的各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 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的降解(通过激活SIRT1酶和 小分子)或抑制其合成(使用酶抑制剂NAMPT)将导致代谢 崩解导致自身的抗肿瘤活性，也可能增加其他 化疗药物。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)的组合 SIRT1激活剂)与吉西他滨联合治疗转移性胰腺癌的临床试验。我们的 该提案极具新颖性，对胰腺新疗法的开发具有重要意义。 癌症。

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.