Two phospho-compounds for pancreatic cancer prevention

 描述（由申请人提供）：胰腺癌（PC）是一种高度侵袭性的癌症，5年生存率<5%。目前的全身标准化疗对患者的益处很小，仅延长了几周的生存期。因此，开发新的PC预防策略变得越来越重要，其中开发新的化学预防剂是最关键的组成部分。我们拟研究两种新型药物[磷酸丙戊酸（P-V）和磷酸阿司匹林（P-A）]，作为预防PC的新药物组合。最近，我们发现P-V在PC的多个临床前模型中强烈抑制PC生长（与对照相比减少高达97%）。遗传毒性和动物毒性研究表明，P-V是安全的，线粒体STAT 3是其关键分子靶点。另一方面，P-A是EGFR活化的强抑制剂，与对照相比，可使PC异种移植物生长减少78%。值得注意的是，当联合给予时，P-A和P-V在具有活化Kras的小鼠中防止胰腺癌的发展达95%（p<0.01）。目的/假设：我们的总体目标是开发一种有效的药物组合用于PC的化学预防。特别强调的是线粒体STAT 3和EGFR信号的参与，这是必不可少的胰腺癌的发生和P-V和P-A的目标。我们的假设是P-V/P-A组合在PC预防中是有效的，协同作用于线粒体STAT 3和EGFR途径。具体目标：我们将追求以下目标：目标#1：评价P-V/P-A组合在PC临床前模型中的安全性、代谢和药代动力学;目标#2：确定P-V/P-A组合在PC临床前模型中的功效;目标#3：确定P-V/P-A组合在体外和体内的作用机制。研究设计：我们的研究将涉及在多个不同但互补的PC临床前模型中评价新型药物组合的安全性、代谢、药代动力学和疗效，并评估该新型药物组合的作用机制。癌症相关性：在完成这些研究时，我们预计已经确定了一种有前景的新型药物组合的关键药理学参数。由于缺乏有效的代理人对PC，我们认为，拟议的工作持有的承诺，在这一领域取得重大进展。

 DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is a highly aggressive cancer with a dismal 5-year survival rate of < 5%. Current systemic standard chemotherapies provide marginal benefits to the patient, only prolonging survival for few weeks. Hence, developing novel preventive strategies for PC assume increase importance, with the development of novel chemopreventive agents being the most critical component. We propose to study two novel agents [phospho-valproic acid (P-V) and phospho-aspirin (P-A)], as a new drug combination for PC prevention. Recently, we showed that P-V strongly inhibits PC growth in multiple preclinical models of PC (up to 97% reduction compared to controls. P-V is safe, as shown by genotoxicity and animal toxicity studies, and mitochondrial STAT3 is its key molecular target. On the other hand, P-A is a strong inhibitor of EGFR activation and reduces PC xenograft growth by 78% compared to control. Remarkably, when given in combination, P-A and P-V prevented the development of pancreatic carcinoma by 95% (p<0.01) in mice with activated Kras. Objective/Hypothesis: Our overall goal is to develop an effective drug combination for the chemoprevention of PC. Particular emphasis is placed on the involvement of mitochondrial STAT3 and EGFR signaling, which are essential for pancreatic carcinogenesis and are targeted by P-V and P-A. Our hypothesis is that the P- V/P-A combination is efficient in PC prevention, acting synergistically on the mitochondrial STAT3 and EGFR pathways. Specific Aims: We will pursue the following aims: Aim #1: To evaluate the safety, metabolism and pharmacokinetics of the P-V/P-A combination in preclinical models of PC; Aim #2: To determine the efficacy of the P-V/P-A combination in preclinical models of PC; Aim #3: To determine the mechanism of action of the P- V/P-A combination in vitro and in vivo. Study design: Our studies will involve the evaluation of the safety, metabolism, pharmacokinetics and efficacy of the novel drug combination in multiple distinct, yet complementary, preclinical models of PC and the assessment of the mechanism of action of this novel drug combination. Cancer relevance: At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel drug combination against PC. Given the lack of effective agents against PC, we believe that the proposed work holds the promise of a significant advance in this area.