Phospho-valproic acid for pancreatic cancer prevention

磷酸丙戊酸预防胰腺癌

• 批准号: 8090488
• 负责人: Basil Rigas
• 金额: $ 31.6万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090488
• 关键词: Animal Model; Animals; Anticonvulsants; Area; Cancer Control; Cancer Etiology; Cancer cell line; Chemoprevention; Chemopreventive Agent; Cimetidine; Clinical; Complex; Data; Development; Growth; Histone Deacetylation; Human; In Vitro; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolism; New Agents; Pathway interactions; Pre-Clinical Model; Prevention; Property; Protocols documentation; STAT3 gene; Safety; Signal Transduction; Signaling Molecule; Testing; Toxic effect; Tumor Volume; Valproic Acid; Work; Xenograft Model; cancer prevention; genotoxicity; in vivo; inhibitor/antagonist; mortality; novel; overexpression; pancreatic cancer cells; pancreatic neoplasm; prevent; public health relevance

DESCRIPTION (provided by applicant): An impressive body of evidence supports the notion that chemoprevention has the potential to be a major component of control of cancer, including pancreatic cancer, one of the most lethal cancers. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid, as an agent for the prevention of pancreatic cancer. P-V inhibits the growth of human cancer cell lines up to 245-fold more potently than VPA. In animal models, P-V is twice as effective against pancreatic cancer as VPA. For example, in xenograft models P-V reduced tumor volume by 68%, compared to control, whereas VPA reduced it by 34% (chemoprevention protocol). Remarkably, when given in combination with cimetidine, a clinically available antiulcer compound, P-V prevented 100% of pancreatic tumors in the same animal model. P-V appears to be safe, as shown by genotoxicity and animal toxicity studies. Its mechanism of action is complex, involving several signaling cascades, most prominently STAT3. Our hypothesis is that P-V 1 cimetidine is an effective and safe chemopreventive agent against pancreatic cancer, acting primarily through the STAT3 pathway. To test this hypothesis, we will pursue the following specific aims: Specific Aim # 1: Determine the chemopreventive efficacy of P-V 1 cimetidine in preclinical models of pancreatic cancer; Specific Aim # 2: Determine the mechanism of action of P-V 1 cimetidine in vitro and in vivo; Specific Aim # 3: Determine the metabolism of P-V 1 cimetidine in cultured pancreatic cancer cells and animals and its safety in animals. At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel agent and its combination with cimetidine. Given the importance of pancreatic cancer and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area. PUBLIC HEALTH RELEVANCE: An impressive body of evidence supports the notion that chemoprevention has the potential to be a major component of control of cancer, including pancreatic cancer, one of the most lethal cancers. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid, as an agent for the prevention of pancreatic cancer. Given the importance of pancreatic cancer and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.

描述（由申请人提供）：大量证据支持化学预防有潜力成为控制癌症（包括最致命的癌症之一胰腺癌）的主要组成部分的观点。我们建议研究磷酸丙戊酸（P-V），一种新型丙戊酸衍生物，作为预防胰腺癌的药物。 P-V 抑制人类癌细胞系生长的能力比 VPA 强 245 倍。在动物模型中，P-V 对抗胰腺癌的效果是 VPA 的两倍。例如，在异种移植模型中，与对照相比，P-V 使肿瘤体积减少了 68%，而 VPA 则使肿瘤体积减少了 34%（化学预防方案）。值得注意的是，当与西咪替丁（一种临床可用的抗溃疡化合物）联合使用时，P-V 在同一动物模型中可以 100% 预防胰腺肿瘤。遗传毒性和动物毒性研究表明，P-V 似乎是安全的。其作用机制很复杂，涉及多个信号级联，其中最突出的是 STAT3。我们的假设是 P-V 1 西咪替丁是一种有效且安全的胰腺癌化学预防剂，主要通过 STAT3 途径发挥作用。为了检验这一假设，我们将追求以下具体目标： 具体目标#1：确定 P-V 1 西咪替丁在胰腺癌临床前模型中的化学预防功效；具体目标#2：确定 P-V 1 西咪替丁的体外和体内作用机制；具体目标#3：确定 P-V 1 西咪替丁在培养的胰腺癌细胞和动物中的代谢及其在动物中的安全性。在这些研究完成后，我们期望确定一种有前途的新药及其与西咪替丁的组合的关键药理学参数。鉴于胰腺癌的重要性以及缺乏有效的治疗药物，我们相信拟议的工作有望在该领域取得重大进展。 公共卫生相关性：大量证据支持这一观点，即化学预防有可能成为控制癌症（包括最致命的癌症之一胰腺癌）的主要组成部分。我们建议研究磷酸丙戊酸（P-V），一种新型丙戊酸衍生物，作为预防胰腺癌的药物。鉴于胰腺癌的重要性以及缺乏有效的治疗药物，我们相信拟议的工作有望在该领域取得重大进展。