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， 诊断以月为单位。胰腺肿瘤的血液供应不发达，导致低血糖。 氧气水平，而他们的快速增长导致他们超过他们的血液供应进一步加剧缺乏 氧气。缺氧对于正常细胞生长是极其不利的环境，但胰腺癌细胞具有 通过增加低氧诱导转录的表达， 因子-1（HIF-1）。由HIF-1诱导的基因通过改变成一种新的蛋白质，使胰腺癌细胞在缺氧中存活。 无氧能量代谢，对程序性细胞死亡（凋亡）产生抗性，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 低氧诱导型HIF-1a亚基和组成型HIF-113亚基的异二聚体。在空气中，HIF-1 α 经历快速的泛素化和蛋白酶体降解，但在缺氧中，降解被抑制， HIF-la水平增加。一些胰腺癌甚至在空气中也显示出HIF-Ia的组成性升高。我们 目前的证据表明，HIF-Ia增加的机制是通过氧化还原水平的增加， 这些蛋白质在胰腺癌中经常升高。当缺氧和HIF-la增加时， 胰腺癌的侵袭性非常强，也是治疗胰腺癌的致命弱点。因此 这项工作所基于的假设是，HIF-1 α的氧化还原调节导致HIF-1 α水平的增加。 胰腺癌中的HIF-1 α是其侵袭性生长和对治疗的抗性的原因， 阻断HIF-1 α的氧化还原调节的药物将具有抗胰腺癌的抗肿瘤活性。我们 已经鉴定了一种新的HIF-1 α小分子抑制剂， 甚至是小鼠中的大的人类胰腺肿瘤异种移植物。我们将进行确定性的实验， 翻译研究，以确定药物抑制胰腺癌中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 控制胰腺癌的生长，并开发新的有效的治疗方法。

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.