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，非甾体抗炎药可以预防胰腺癌，但流行病学研究存在矛盾，这可能反映了传统非甾体抗炎药缺乏足够的疗效。值得注意的是，非甾体抗炎药的副作用阻碍了它们在癌症预防方面的大规模应用。新型一氧化氮释放阿司匹林（NO-ASA）由一个ASA分子和一个通过化学间隔剂连接的no释放片段组成。NO-ASA有三种位置异构体（邻位、间位和对位）。两项研究证明了它对人体的安全性。我们观察到no -阿司匹林（NO-ASA）在抑制培养胰腺癌细胞生长方面的效力是ASA的695倍。我们的初步研究还表明，在致癌物BOP处理的仓鼠中，NO-ASA抑制胰腺癌的形成率为89.9%。这些发现结合其优越的疗效和安全性，使NO-ASA成为一种有前景的化学预防药物，并为研究其在胰腺癌发生中的作用机制提供了有力的论据。我们建议评估两个假设：a) NO-ASA是一种胰腺癌的化学预防剂，b) NO-ASA抑制胰腺中的NF-kappaB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-kappaB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。

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.