Role of HIF-1 alpha in EcSOD-Induced Growth Inhibition of Pancreatic Cancer

HIF-1 α 在 EcSOD 诱导的胰腺癌生长抑制中的作用

• 批准号: 8764691
• 负责人: Joseph J Cullen
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764691
• 关键词: 5 year old; Address; Age; Cancer Cell Growth; Cancer Etiology; Cancer cell line; Caring; Cessation of life; Chemicals; Clinical Trials; Data; Development; Diagnosis; Disease; Dominant-Negative Mutation; Drug Targeting; Erythropoiesis; Excision; Fluorouracil; Foundations; Gene Targeting; Glycolysis; Growth; HIF1A gene; Health; Human; Hypoxia Inducible Factor; In Vitro; Incidence; Left; Life; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Medicine; Mission; Operative Surgical Procedures; Pancreatic Adenocarcinoma; Patient Care; Patients; Population; Pre-Clinical Model; Process; Procollagen-Proline Dioxygenase; Radiation therapy; Regimen; Reporting; Research; Role; Small Interfering RNA; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Tumor Suppression; United States; Veterans; angiogenesis; antioxidant enzyme; cancer cell; cell growth; chemotherapeutic agent; chemotherapy; combined cancer modality therapy; design; effective therapy; expression vector; extracellular; gemcitabine; improved; in vivo; inhibitor/antagonist; malignant phenotype; neoplastic cell; novel; overexpression; pancreatic cancer cells; programs; standard of care; tempol; therapeutic target; transcription factor; treatment strategy; tumor

DESCRIPTION (provided by applicant): Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Because of the poor therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy, survival beyond five years is rare with median survival less than six months. Thus, novel and effective therapies directed against pancreatic cancer are needed to control progression and metastatic disease. Our studies have shown that scavenging superoxide with the antioxidant enzyme extracellular superoxide dismutase (EcSOD) or pharmacologically with the nitroxide compound tempol, have a strong tumor-suppressive effect in pancreatic cancer both in vitro and in vivo. New data presented in this proposal shows that overexpression of EcSOD leads to suppression of hypoxia inducible factor- 1a (HIF-1a). HIF-1a responds to reduced O2 availability by regulating crucial homeostatic processes such as angiogenesis, glycolysis, and erythropoiesis and has been suggested to be an important regulator of pancreatic cancer cell progression and survival. As a transcription factor, HIF-1 has more than 80 known target genes and the number continues 1. Determine whether the effects of EcSOD overexpression on pancreatic cancer cell growth inhibition are due to HIF-1a suppression by manipulating HIF-1a levels genetically and pharmaceutically. to increase. The current proposal will test the hypothesis that themechanism for the tumor suppressive effect of EcSOD and/or tempol is caused inlarge part due to the suppression of HIF-1 in pancreatic cancer and that this suppression is due to the removal of superoxide. In order to examine this hypothesis, we will address the following three Specific Aims: 2. Determine if pharmacological scavenging of superoxide in human pancreatic cancer cells with Tempol mimics the effects observed with EcSOD on HIF-1a. 3. Determine if Tempol-induced growth inhibition can be enhanced by chemotherapeutic agents (gemcitabine, 5-FU) in human pancreatic cancer. As reported in a recent NCI cancer bulletin article on pancreatic cancer, ¿the slow but steady march toward more individualized care in cancer medicine has left pancreatic cancer behind. Patients diagnosed with this disease live no longer today than patients diagnosed two decades ago, despite more than a dozen large clinical trials. Even as many patients with other cancers have benefited from targeted drugs, pancreatic cancer remains as deadly as ever¿ (http://www.cancer.gov/ncicancerbulletin/110309/page1). If we can rigorously demonstrate that the tumor suppressive effect of EcSOD and/or tempol is caused in large part by the suppression of HIF-1 in pancreatic cancer then the results of this proposed research program will provide a foundation for the rational design of a combined modality cancer therapy.

描述（由申请人提供）： 胰腺腺癌是美国癌症死亡的第四大原因，并且发病率正在增加。由于胰腺癌对手术、化疗和放疗的治疗反应性差，生存期超过5年的情况很少见，中位生存期不到6个月。因此，需要针对胰腺癌的新型有效疗法来控制进展和转移性疾病。我们的研究表明，清除超氧化物与抗氧化酶细胞外超氧化物歧化酶（EcSOD）或与氮氧化物化合物tempol，有很强的肿瘤抑制作用，在胰腺癌在体外和体内。该提案中提出的新数据表明，EcSOD的过表达导致缺氧诱导因子-1a（HIF-1a）的抑制。HIF-1a通过调节重要的稳态过程如血管生成、糖酵解和红细胞生成来响应减少的O2可用性，并且已被认为是胰腺癌细胞进展和存活的重要调节剂。作为一种转录因子，HIF-1已知的靶基因有80多个，其数量在100个以上。通过基因和药物调控HIF-1a水平，确定EcSOD过表达对胰腺癌细胞生长抑制的影响是否是由于HIF-1a抑制。 增加。目前的建议将测试这一假设，即EcSOD和/或tempol的肿瘤抑制作用的机制在很大程度上是由于胰腺癌中HIF-1的抑制而引起的，并且这种抑制是由于清除超氧化物。为了检验这一假设，我们将讨论以下三个具体目标：2。确定Tempol对人胰腺癌细胞中超氧化物的药理学清除是否模拟了EcSOD对HIF-1a的影响。 3.确定化疗药物（吉西他滨，5-FU）是否可以增强Tempol诱导的人胰腺癌生长抑制。 正如最近NCI癌症公告中关于胰腺癌的文章所报道的那样，在癌症医学中，朝着更加个性化的护理方向缓慢而稳步地前进，已经把胰腺癌抛在了后面。尽管进行了十几次大型临床试验，但今天诊断出患有这种疾病的患者的寿命并不比20年前诊断出的患者长。即使许多患有其他癌症的患者受益于靶向药物，胰腺癌仍然像以往一样致命（http：//www.cancer.gov/ncicancerbulletin/110309/page1）。如果我们能够严格证明EcSOD和/或tempol的肿瘤抑制作用在很大程度上是由胰腺癌中HIF-1的抑制引起的，那么这项拟议的研究计划的结果将为合理设计联合治疗癌症提供基础。