A novel combination approach for pancreatic cancer prevention

 描述（由申请人提供）：胰腺癌是一种复杂而致命的疾病，5年生存率低（<5%）。由于它通常在晚期被诊断出来，没有治愈性治疗，因此开发新的策略来预防或延迟胰腺癌的进展至关重要。我们建议研究磷酸丙戊酸（P-V），一种新的丙戊酸（VPA）的衍生物，与西咪替丁，一种临床上可用的抗溃疡化合物，作为一种新的药物组合，用于胰腺癌的预防。P-V对胰腺癌的疗效是VPA的两倍。例如，在异种移植模型中，与对照相比，P-V使肿瘤生长减少68%，而VPA使其减少34%（化学预防方案）。值得注意的是，当与西咪替丁联合给药时，P-V在相同的动物模型中完全阻止胰腺肿瘤的生长。如遗传毒性和动物毒性研究所示，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STAT 3。我们的假设是P-V +西咪替丁是一种有效和安全的胰腺癌化学预防药物组合。为了检验这一假设，我们将追求以下具体目标：目标#1：确定P-V +西咪替丁在胰腺癌临床前模型中的化学预防功效;目标#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，我们期望已经确定了一种有前途的预防胰腺癌的新型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剂，我们相信，拟议的工作在这一领域取得重大进展的承诺。

 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.