A novel combination approach for pancreatic cancer prevention

预防胰腺癌的新组合方法

• 批准号: 9404126
• 负责人: Gerardo Guillermo Mackenzie
• 金额: $ 6.28万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-23 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9404126
• 关键词: novel; combination; approach; pancreatic; cancer

 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.

 描述（由适用提供）：胰腺癌是一种复杂而致命的疾病，其5年生存率（<5％）。由于通常在没有治疗疗法的高级阶段被诊断出来，因此制定了预防或延迟胰腺癌进展的新型策略至关重要。我们建议研究一种新型丙戊酸（VPA）的磷酸化磷酸 - 瓦戊酸（P-V），并结合甲甲苯烷（一种临床上可用的抗硫酸盐化合物），作为一种新型的胰腺癌预防药物组合。 P-V对胰腺癌的有效性是VPA的两倍。例如，在异种移植模型中，与对照相比，P-V减少了68％的肿瘤生长，而VPA则将其降低34％（化学预防方案）。值得注意的是，当与甲依然丁结合使用时，P-V完全防止了同一动物模型中胰腺肿瘤的生长。如遗传毒性和动物毒性研究所示，P-V似乎是安全的，其关键作用机理是在线粒体水平上抑制STAT3。我们的假设是P-V + Cimetidine是针对胰腺癌的有效且安全的化学预防药物组合。为了检验这一假设，我们将追求以下特定目的：目标＃1：确定P-V + Cimetidine在胰腺癌的临床前模型中的化学预防有效性； AIM＃2：确定体外和体内P-V + Cimetidine的作用机理。这些研究完成后，我们希望确定有望预防胰腺癌的新型药物组合方法的关键药物参数。鉴于胰腺癌的重要性以及缺乏有效的化学预防剂对抗，我们认为拟议的工作有望在这一领域取得重大进展。