Pancreatic cancer prevention with NO-releasing NSAIDs

描述（由申请人提供）：化学预防可以是控制胰腺癌的主要组成部分，胰腺癌是最致命的恶性肿瘤之一。临床前数据表明，NSAID预防胰腺癌，但流行病学研究是相互矛盾的，可能反映了传统NSAID缺乏足够的疗效。值得注意的是，NSAID的副作用阻碍了其在癌症预防中的大规模应用。新型一氧化氮释放阿司匹林（NO-ASA）由阿萨分子和通过化学间隔基连接的NO释放部分组成。NO-ASA有三种位置异构体（邻位、Meta和帕拉）。两项研究证明了其对人体的上级安全性。我们已经观察到NO-阿司匹林（NO-ASA）在抑制培养的胰腺癌细胞生长方面比阿萨强695倍。我们的初步研究还表明，NO-ASA在用致癌物BOP治疗的仓鼠中抑制了89.9%的胰腺癌形成。这些发现结合其上级疗效和安全性，使NO-ASA成为一种有前途的化学预防剂，并构成了一个令人信服的论据，研究其在胰腺癌发生中的作用机制。我们建议评估两个假设：a）NO-ASA是胰腺癌的化学预防剂，和B）NO-ASA抑制胰腺中的NF-κ B通路，并且这种作用在很大程度上解释了其预防胰腺癌的能力。NF-κ B激活是胰腺癌发生的关键事件，我们的初步数据表明，NO-ASA强烈抑制它。 我们将研究NO-ASA的三种位置异构体。我们的具体目标是：1）在培养的胰腺癌细胞中确定NO-ASA对NF-κ B通路的影响。具体而言，我们将研究NO-ASA对NF-κ B激活的抑制作用并确定其机制; NO-ASA对胰腺癌细胞动力学的影响，并确定这种影响是否需要NF-κ B抑制;评估介导NF-κ B依赖性基因的表达;并确定NO-ASA分子的哪一部分对NF-κ B的作用至关重要。基于该特定目标的结果，我们将选择最有希望的NO-ASA位置异构体以：2）在胰腺癌动物模型中确定NO-ASA对胰腺癌发生的功效，并阐明其对NF-κ B的体内作用。具体而言，我们将确定胰腺肿瘤的发病率和多样性; NF-κ B活化的抑制;对细胞增殖、凋亡和介导这种效应的相关NF-κ B依赖基因的影响。这些研究将提供机制数据和详细的临床前评价，为NO-ASA治疗胰腺癌的临床评估奠定基础。

DESCRIPTION (provided by applicant): Chemoprevention can be a major component of the control of pancreatic cancer, one of the deadliest malignancies. Preclinical data indicate that NSAIDs prevent pancreatic cancer, but epidemiological studies are conflicting, perhaps reflecting lack of sufficient efficacy by traditional NSAIDs. Of note, NSAID side effects preclude their large-scale application in cancer prevention. The novel nitric oxide-releasing aspirin (NO-ASA) consists of an ASA molecule and a NO-releasing moiety linked via a chemical spacer. There are three positional isomers of NO-ASA (ortho, meta and para). Two studies have documented its superior safety in humans. We have observed that NO-aspirin (NO-ASA) is 695-fold more potent than ASA in inhibiting the growth of cultured pancreatic cancer cells. Our preliminary study also shows that NO-ASA inhibits pancreatic cancer formation by 89.9% in hamsters treated with the carcinogen BOP. These findings combined with its superior efficacy and safety, make NO-ASA a promising chemopreventive agent and constitute a compelling argument to study its mechanism of action in pancreatic carcinogenesis. We propose to evaluate two hypotheses: a) that NO-ASA is a chemopreventive agent against pancreatic cancer, and b) that NO-ASA inhibits the NF-kappaB pathway in the pancreas and that this effect accounts, to a significant degree, for its ability to prevent pancreatic cancer. NF-kappaB activation is a key event in pancreatic carcinogenesis and our preliminary data indicate that NO-ASA strongly inhibits it. We will study the three positional isomers of NO-ASA. Our specific aims are: 1) Determine in cultured pancreatic cancer cells the effect of NO-ASA on the NF-kappaB pathway. Specifically, we will study the inhibition of NF-kappaB activation by NO-ASA and determine its mechanism; the effect of NO-ASA on pancreatic cancer cell kinetics and determine whether NF-kappaB inhibition is required for this effect; assess the expression of NF-kappaB dependent genes that mediate it; and determine which part of the NO-ASA molecule is critical for its effect on NF-kappaB. Based on the results of this Specific Aim, we will select the most promising NO-ASA positional isomer to: 2) Determine in an animal model of pancreatic cancer the efficacy of NO-ASA against pancreatic carcinogenesis and elucidate its in vivo effect on NF-kappaB. Specifically, we will determine in the pancreas tumor incidence and multiplicity; inhibition of NF-kappaB activation; effects on cell proliferation, apoptosis and relevant NF-kappaB dependent genes that mediate this effect. These studies will provide mechanistic data and a detailed preclinical evaluation, setting the stage for the clinical assessment of NO-ASA against pancreatic cancer.