A novel combination approach for pancreatic cancer prevention

 描述(申请人提供)：胰腺癌是一种复杂而致命的疾病，5年生存率很低(&lt；5%)。由于胰腺癌通常被诊断为晚期，没有根治方法，因此开发新的策略来预防或延缓胰腺癌的进展是至关重要的。我们建议研究丙戊酸(VPA)的新型衍生物磷酸丙戊酸(P-V)与临床上可用的抗溃疡化合物西咪替丁联合作为预防胰腺癌的新药物组合。P-V对胰腺癌的疗效是VPA的两倍。例如，在异种移植模型中，与对照组相比，P-V可使肿瘤生长减少68%，而VPA可使其减少34%(化学预防方案)。值得注意的是，当P-V与西咪替丁联合使用时，在相同的动物模型中，P-V完全阻止了胰腺肿瘤的生长。遗传毒性和动物毒性研究表明，P-V似乎是安全的，其关键作用机制是在线粒体水平上抑制STAT3。我们的假设是P-V+西咪替丁是一种有效、安全的胰腺癌化学预防药物组合。为了验证这一假设，我们将追求以下具体目标：目的1：确定P-V+西咪替丁在胰腺癌临床前模型中的化学预防效果；目的2：确定P-V+西咪替丁在体外和体内的作用机制。在这些研究完成后，我们期望确定一种有前景的预防胰腺癌的新药物组合方法的关键药理学参数。鉴于胰腺癌的重要性和缺乏有效的化学预防药物，我们相信拟议的工作有望在这一领域取得重大进展。

 DESCRIPTION (provided by applicant): Pancreatic cancer is a complex and lethal disease with a dismal 5-year survival rate (<5%). Because it is usually diagnosed in an advanced stage with no curative therapies, developing novel strategies to prevent or delay the progression of pancreatic cancer is of utmost importance. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid (VPA), in combination with cimetidine, a clinically available antiulcer compound, as a novel drug combination for pancreatic cancer prevention. P-V is twice as effective against pancreatic cancer as VPA. For example, in xenograft models P-V reduces tumor growth by 68%, compared to control, whereas VPA reduces it by 34% (chemoprevention protocol). Remarkably, when given in combination with cimetidine, P-V completely prevents the growth of pancreatic tumors in the same animal model. P-V appears to be safe, as shown by genotoxicity and animal toxicity studies, and its key mechanism of action is the inhibition of STAT3 at the mitochondrial level. Our hypothesis is that P-V + cimetidine is an effective and safe chemopreventive drug combination against pancreatic cancer. To test this hypothesis, we will pursue the following specific aims: Aim # 1: Determine the chemopreventive efficacy of P-V + cimetidine in preclinical models of pancreatic cancer; Aim # 2: Determine the mechanism of action of P-V + cimetidine in vitro and in vivo. At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel drug combination approach for pancreatic cancer prevention. Given the importance of pancreatic cancer and the lack of effective chemopreventive agents against it, we believe that the proposed work holds the promise of a significant advance in this area.