Targeting NADPH Oxidase for Pancreatic Cancer Prevention and Therapy

胰腺导管腺癌(PDAC)正迅速成为与癌症相关的第二大病因。 美国的死亡。PDAC的基因图景显示KRAS的普遍突变；然而，表达 仅在成年阶段突变的KRAS(KRASmt)不足以驱动PDAC，这表明第二次命中是 必填项。KRASmt以前被认为是癌基因，被认为是完全活跃的，但最近的研究 已经表明KRASmt的内源性水平并不是完全活跃的。相反，它可以被胰腺过度激活。 癌症风险因素，包括胰腺炎和肥胖的高脂饮食挑战，这是第二个打击 推广高外显度的PDAC。然而，将这些危险因素与KRASmt联系起来的分子介质 过度激活仍然难以捉摸。NADPH氧化酶(NOX)是KRASmt激活的主要酶。 癌症中活性氧物种的产生和氧化应激。值得注意的是，我们的初步数据显示 对NOX的抑制抑制了KRASmt的激活，这表明NOX不仅是下游的效应器，而且 也是KRASmt潜在的上游监管机构。基于这些观察，我们假设胰腺 癌症危险因素，包括胰腺炎和长期高脂饮食的摄入，促进了 持续的NOX和KRASmt共同激活伙伴关系，从而实现全面的PDAC。靶向抑制 NOx破坏了这些风险因素促进的伙伴关系，从而阻碍了胰腺肿瘤的发生。为了测试 在这个假设下，我们将使用新的可诱导的基因工程小鼠模型来表达内源性 去除胰腺腺泡细胞中NOX对接亚基p22Phox后KrasG12D水平的变化及暴露小鼠 炎性刺激或肥胖的高脂肪饮食。同样，突变型P53也促进了NOX-KrasG12D的协同作用。 激活合作伙伴关系，以促进积极的PDAC。我们将消融胰腺腺泡细胞中的p22Phox。 同时表达KrasG12D/+和p53R172H/+的小鼠。该提案的目标是确定NOX是否是有害气体 将这些胰腺癌风险因子与KRASmt过度激活联系起来的真正关键分子介质，它 推动胰腺肿瘤的进展，这是胰腺癌领域一个基本的尚未回答的问题。如果 事实证明，这项研究将描绘出协同合作的分子基础和细胞事件 在致癌的KRAS、NOX和胰腺癌危险因素中，并将为新的预防措施提供见解 以及针对人类这种毁灭性疾病的治疗策略。

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.