Pancreatic cancer prevention with NO-releasing NSAIDs

描述(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，非类固醇抗炎药可预防胰腺癌，但流行病学研究相互矛盾，可能反映了传统非类固醇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中的大规模应用。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连接的NO释放部分组成。NO-ASA有三种位置异构体(邻位、间位和对位)。两项研究已经证明了它在人体上的卓越安全性。我们观察到，非阿司匹林(NO-ASA)在抑制培养的胰腺癌细胞生长方面的效力是ASA的695倍。我们的初步研究还显示，在用致癌物BOP治疗的仓鼠中，NO-ASA对胰腺癌的形成抑制了89.9%。这些发现结合其优越的有效性和安全性，使NO-ASA成为一种有前途的化学预防药物，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是一种预防胰腺癌的化学预防药物，b)NO-ASA抑制胰腺中的NF-kappaB途径，这种作用在很大程度上解释了它预防胰腺癌的能力。核因子-kappaB的激活是胰腺癌发生过程中的一个关键事件，我们的初步数据表明NO-ASA强烈地抑制了它的激活。 我们将研究NO-ASA的三个位置异构体。我们的具体目标是：1)在培养的胰腺癌细胞中检测NO-ASA对核因子-kappaB途径的影响。具体地说，我们将研究NO-ASA对NF-kappaB活性的抑制并确定其机制；NO-ASA对胰腺癌细胞动力学的影响并确定是否需要抑制NF-kappaB来实现这一作用；评估介导其激活的依赖于NF-kappaB的基因的表达；以及确定NO-ASA分子中的哪一部分对其对NF-kappaB的影响至关重要。根据这一特定目的的结果，我们将选择最有前景的NO-ASA位置异构体：2)在胰腺癌动物模型上测定NO-ASA的抗胰腺癌作用，并阐明其对核因子-kappaB的体内作用。具体地说，我们将确定在胰腺肿瘤的发生率和多发性；抑制核因子-kappaB的激活；对细胞增殖、凋亡的影响以及介导这一作用的相关核因子-kappaB依赖基因。这些研究将提供机制数据和详细的临床前评估，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.