Treatment of Hypoxia Resistance in Pancreatic Cancer - Clinical

胰腺癌耐缺氧的治疗。胰腺癌是最具侵袭性的成人实体之一。 肿瘤和患者在确诊时的存活率以月为单位进行衡量。胰腺肿瘤的血液发育不良。 供应导致低氧水平，而它们的快速生长则使它们进一步超出其血液供应 加重了缺氧的程度。低氧对正常细胞生长是极其不利的环境，但胰腺 癌细胞通过增加低氧诱导蛋白的表达而适应在低氧环境中生长。 转录因子1(HIF-1)。HIF-1诱导的基因改变使胰腺癌细胞耐低氧存活 到无氧能量代谢，对程序性细胞死亡(细胞凋亡)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是一种杂二聚体 低氧诱导的HIF-1a亚基和构成HIF-1a的亚基。在空气中，HIF-la经历了快速 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水平增加。 一些胰腺癌甚至在空气中也表现出结构性的HIF-1a升高。我们提出的证据表明，一种 HIF-1a的增加是通过增加氧化还原蛋白的水平来实现的，而氧化还原蛋白在 胰腺癌。虽然缺氧和HIF-1a的增加使胰腺癌非常具有侵袭性，但它也提供了 治疗这种疾病的致命弱点。因此，这项工作所基于的假设是氧化还原调节 HIF-1a在胰腺癌中导致HIF-1水平升高是胰腺癌侵袭性生长和 耐药，阻断HIF-1氧化还原调节的药物将具有抗肿瘤活性 胰腺癌。我们已经确定了两种新的HIF-1a小分子抑制剂，它们显示出互补的 对小鼠人胰腺癌移植瘤的抗肿瘤活性。我们将进行最终的实验和 确定药物抑制胰腺癌中HIF-1a的机制的翻译研究 这些药物在胰腺癌患者中的临床试验。我们工作的长期目标是了解 氧化还原控制胰腺癌的生长，并开发新的有效的疾病治疗方法。

Treatment of Hypoxia Resistance in Pancreatic Cancer. 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 an 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 programed 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 the hypoxia-inducibleHIF-la subunit and a constitutive HIF-1a 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-1 in pancreatic cancer is responsiblefor its aggressive growth and resistance to therapy, and that drugs that block the redox regulation of HIF-1 will have antitumor activity against pancreatic cancer. We have identified two novel small molecule inhibitors of HIF-la that shows complimentary antitumor activity against human pancreatic tumor xenografts in mice. We will perform definitive experimental and translational studies to identify the mechanism by which the drugs inhibit HIF-la in pancreatic cancer and conduct clinical trials with the agents in patients with pancreatic cancer. The long term objective of our work is to understand the redox control of pancreatic cancer growth and to develop novel and effective treatments for the disease.