Phospho-valproic acid for pancreatic cancer prevention

描述（由申请人提供）：大量令人印象深刻的证据支持这样一种观点，即化学预防有可能成为控制癌症的主要组成部分，包括最致命的癌症之一胰腺癌。我们建议研究丙戊酸的新衍生物磷酸丙戊酸（P-V）作为预防胰腺癌的药物。P-V对人类癌细胞系的抑制作用是VPA的245倍。在动物模型中，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使肿瘤体积减少了68%，而VPA使肿瘤体积减少了34%（化学预防方案）。值得注意的是，当P-V与临床上可用的抗溃疡化合物西咪替丁联合使用时，在同一动物模型中，P-V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。它的作用机制是复杂的，涉及几个信号级联，最突出的是STAT3。我们的假设是p - v1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途径起作用。为了验证这一假设，我们将追求以下具体目标：具体目标# 1：确定p - v1西咪替丁在胰腺癌临床前模型中的化学预防功效；特异性目的# 2：确定p - v1西咪替丁的体内外作用机制；特异性目的# 3：确定p - v1西咪替丁在培养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景的新型药物及其与西咪替丁的联合的关键药理学参数。鉴于胰腺癌的重要性和缺乏有效的药物对抗它，我们相信提出的工作有希望在这一领域取得重大进展。

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.