Treatment of Hypoxia Resistance in Pancreatic Cancer -Lab

项目1：胰腺癌是最具侵袭性的成人实体瘤之一，患者存活率在 诊断以月为单位进行衡量。胰腺肿瘤的血液供应不发达，导致低血症。 氧气水平，而他们的快速增长导致他们超过了他们的血液供应，进一步加剧了缺乏 氧气。低氧对正常细胞生长极为不利，但胰腺癌细胞 通过增加低氧诱导转录的表达来适应在低氧中茁壮成长 因子-1(HIF-1)。HIF-1诱导的基因使胰腺癌细胞在低氧状态下存活 无氧能量代谢，对细胞程序性死亡(凋亡)产生抵抗力，产生细胞因子 促进新的肿瘤毛细血管的形成(血管生成)和转移。HIF-1是 低氧诱导的HIF-1a亚基和HIF-113亚基的异源二聚体。在空中，Hif-la 经历快速泛素化和蛋白酶体降解，但在低氧条件下，降解受到抑制 HIF-1a水平升高。一些胰腺癌甚至在空气中也表现出结构性的HIF-1a升高。我们 目前有证据表明，HIF-1a增加的机制是通过增加氧化还原水平 在胰腺癌中经常升高的蛋白质。而缺氧和HIF-1a的增加使 胰腺癌非常具有侵袭性，它也为治疗这种疾病提供了一个致命弱点。因此， 这项工作所基于的假设是，HIF-1a的氧化还原调节导致血浆中 胰腺癌中的HIF-1a是其侵袭性生长和对治疗的抵抗的原因，而 阻断HIF-1a氧化还原调节的药物将对胰腺癌具有抗肿瘤活性。我们 已经确定了一种新的HIF-1a小分子抑制剂，它具有显著的抗肿瘤活性 甚至在小鼠体内移植了巨大的人胰腺肿瘤。我们将进行最终的实验和 翻译研究以确定该药物抑制胰腺癌HIF-1ct的机制 在胰腺癌患者中进行临床试验。长期目标是了解氧化还原过程。 控制胰腺癌的生长，并为这种疾病开发新的有效治疗方法。

Project 1: Pancreatic cancer is one of the most aggressive adult solid tumors and patient survival at diagnosis is measured in months. Pancreatic tumors have a poorly developed blood supply leading to low oxygen levels while their rapid growth causes them to outstrip their blood supply further aggravating the lack of oxygen. Hypoxia is extremely hostile environment for normal cell growth but pancreatic cancer cells have adapted to thrive in low oxygen through the increased expression of the hypoxia inducible transcription factor-1 (HIF-1). Genes induced by HIF-1 allow pancreatic cancer cells to survive hypoxia by changing to an anaerobic energy metabolism, to become resistant to programmed cell death (apoptosis), to produce cytokines that promote the formation of new tumor capillary blood vessels (angiogenesis) and to metastasize. HIF-1 is a heterodimer of a hypoxia-inducible HIF-la subunit and a constitutive HIF-113 subunit. In air, HIF-la undergoes rapid ubiquitination and proteasomal degradation but in hypoxia the degradation is inhibited and HIF-la levels increase. Some pancreatic cancers show constitutive elevation of HIF-la even in air. We present evidence that a mechanism for the increase in HIF-la is through an increase in the levels of the redox proteins that are frequently elevated in pancreatic cancer. While hypoxia and increases in HIF- la makes pancreatic cancers very aggressive it also provides an achilles heel for treating the disease. Thus, the hypothesis upon which the work is based is that the redox regulation of HIF-la leading to increased levels of HIF-la in pancreatic cancer is responsible for their aggressive growth and resistance to therapy, and that drugs that block the redox regulation of HIF-la will have antitumor activity against pancreatic cancer. We have identified a novel small molecule inhibitor of HIF-1 a that shows remarkable antitumor activity against even large human pancreatic tumor xenografts in mice. We will perform definitive experimental and translational studies to identify the mechanism by which the drug inhibits HIF- 1ct in pancreatic cancer and conduct clinical trial in patients with pancreatic cancer. The long term objective is to understand the redox control of pancreatic cancer growth and to develop novel and effective treatments for the disease.