Targeting NADPH Oxidase for Pancreatic Cancer Prevention and Therapy

以 NADPH 氧化酶为靶点预防和治疗胰腺癌

• 批准号: 10226904
• 负责人: Weiqin Lu
• 金额: $ 36.18万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10226904
• 关键词: Ablation; Acinar Cell; Adult; Cancer Etiology; Cessation of life; Chronic; Consumption; Data; Development; Disease; Docking; Enzymes; Event; Exposure to; Generations; Genetic; Genetically Engineered Mouse; High Fat Diet; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; KRAS2 gene; KRASG12D; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modification; Molecular; Mouse Strains; Mus; Mutation; NADPH Oxidase; Obesity; Oncogenes; Oncogenic; Oranges; Outcome; Oxidation-Reduction; Oxidative Stress; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatitis; Pathologic; Penetrance; Prevention; Prevention therapy; Preventive; Reactive Oxygen Species; Reporting; Risk Factors; Stimulus; TP53 gene; Testing; Therapeutic; United States; base; design; dietary; in vivo; insight; mutant; novel; obesogenic; pancreatic tumorigenesis; systemic inflammatory response; tumor progression

Pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming the second leading cause of cancer-related deaths in the U.S. The genetic landscape of PDAC shows prevalent mutations of KRAS; however, expression of mutant KRAS (KRASmt) alone at the adult stage is insufficient to drive PDAC, suggesting that a second hit is required. KRASmt was previously regarded as an oncogene and thought to be fully active, yet recent studies have shown that an endogenous level of KRASmt is not fully active. Rather, it can be hyperactivated by pancreatic cancer risk factors, including pancreatitis and obesogenic high-fat diet challenge, which act as the second hit to promote PDAC with high penetrance. However, the molecular mediator linking these risk factors to KRASmt hyperactivation remains elusive. NADPH oxidases (NOX) are major enzymes activated by KRASmt for the generation of reactive oxygen species and oxidative stress in cancer. Notably, our preliminary data have shown that inhibition of NOX suppresses KRASmt activation, indicating that NOX is not only a downstream effector but also a potential upstream regulator of KRASmt. Based on these observations, we hypothesize that pancreatic cancer risk factors, including pancreatitis and chronic high-fat diet consumption, facilitate the formation of a sustained NOX and KRASmt co-activation partnership, which leads to full-blown PDAC. Targeted inhibition of NOX breaks the partnership promoted by these risk factors, thus hampering pancreatic tumorigenesis. To test this hypothesis, we will employ novel inducible genetically engineered mouse models expressing endogenous levels of KRASG12D with ablation of NOX docking subunit p22phox in pancreatic acinar cells and expose the mice to inflammatory stimuli or obesogenic high-fat diet. Similarly, mutant p53 also facilitates the NOX-KRASG12D co- activation partnership to promote aggressive PDAC. We will ablate p22phox in pancreatic acinar cells of the mice expressing both KrasG12D/+ and p53R172H/+. The objective of this proposal is to determine if NOX is the bona fide critical molecular mediator linking these pancreatic cancer risk factors to KRASmt hyperactivation, which drives pancreatic neoplastic progression, a fundamental unanswered question in the pancreatic cancer field. If proven, this study will delineate the molecular underpinnings and cellular events of the synergistic cooperation among oncogenic KRAS, NOX, and pancreatic cancer risk factors, and will provide insights into novel preventive and therapeutic strategies against this devastating disease in humans.

胰腺导管腺癌（PDAC）正在迅速成为癌症相关性的第二大原因。 PDAC的遗传景观显示KRAS的普遍突变;然而， 成年阶段单独突变KRAS（KRASmt）不足以驱动PDAC，这表明第二次击中是 必需的. KRASmt以前被认为是一种癌基因，并被认为是完全活跃的，但最近的研究表明， 已经表明KRASmt的内源性水平并不完全活跃。相反，它可以被胰腺炎过度激活， 癌症风险因素，包括胰腺炎和致肥胖高脂肪饮食挑战，这是第二次打击， 促进PDAC高转化率。然而，将这些风险因素与KRASmt联系起来的分子介导物 超激活仍然难以捉摸。NADPH氧化酶（NOX）是KRASmt激活的主要酶， 癌症中活性氧的产生和氧化应激。值得注意的是，我们的初步数据显示， 抑制NOX抑制KRASmt活化，表明NOX不仅是下游效应物， 也是KRASmt的潜在上游监管机构。基于这些观察结果，我们假设胰腺癌患者的胰腺 癌症风险因素，包括胰腺炎和慢性高脂肪饮食消费，促进了 持续的NOX和KRASmt共激活伙伴关系，从而导致全面的PDAC。靶向抑制 NOX破坏了这些危险因素促进的伙伴关系，从而阻碍了胰腺肿瘤的发生。测试 基于这一假设，我们将采用新的诱导型基因工程小鼠模型， KRASG 12 D水平与胰腺腺泡细胞中NOX对接亚基p22 phox的消融以及暴露小鼠 炎症刺激或致肥高脂饮食。类似地，突变型p53也促进了NOX-KRASG 12 D共表达。 激活合作伙伴关系，促进积极的PDAC。我们将切除胰腺腺泡细胞中的p22 phox， 同时表达KrasG 12 D/+和p53 R172 H/+的小鼠。本提案的目的是确定NOX是否是 真正的关键分子介质，将这些胰腺癌风险因素与KRASmt过度活化联系起来， 驱动胰腺肿瘤进展，这是胰腺癌领域的一个基本未回答的问题。如果 证明，这项研究将描绘协同合作的分子基础和细胞事件 在致癌KRAS，NOX和胰腺癌风险因素中， 和治疗策略来对抗这种毁灭性的疾病。