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肿瘤之一， 诊断时的肿瘤和患者存活以月为单位测量。胰腺肿瘤的血液不发达 供应导致低氧水平，而它们的快速生长导致它们进一步超过血液供应 加剧了缺氧。缺氧是一个非常不利的环境，正常细胞生长，但胰腺 癌细胞已经适应了在低氧下通过增加低氧诱导的 转录因子-1（HIF-1）。由HIF-1诱导的基因通过改变胰腺癌细胞的生长状态， 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是一种异源二聚体 缺氧诱导的HIF-1 α亚基和组成型HIF-1 α亚基。在空气中，HIF-la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-1 α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。我们提出的证据表明， HIF-1 α的增加是通过氧化还原蛋白水平的增加， 胰腺癌虽然缺氧和HIF-Ia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，这项工作所依据的假设是， 导致胰腺癌中HIF-1水平升高的HIF-1a是胰腺癌侵袭性生长的原因， 阻断HIF-1的氧化还原调节的药物将具有抗肿瘤活性， 胰腺癌我们已经鉴定了两种新的HIF-Ia的小分子抑制剂，其显示出互补性。 在小鼠中对人胰腺肿瘤异种移植物的抗肿瘤活性。我们将进行确定性的实验， 翻译研究以鉴定药物抑制胰腺癌中HIF-Ia的机制，并进行 在胰腺癌患者中进行的药物临床试验。我们工作的长期目标是了解 胰腺癌生长的氧化还原控制，并开发新的和有效的治疗方法。

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.