Two phospho-compounds for pancreatic cancer prevention

 描述(申请人提供)：胰腺癌(PC)是一种高度侵袭性的癌症，5年生存率很低，仅为5%。目前的全身标准化疗给患者带来的益处微乎其微，仅能延长几周的生存时间。因此，开发新的PC预防策略变得越来越重要，而开发新的化学预防药物是最关键的组成部分。我们建议研究两种新的药物[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，我们发现在多种PC临床前模型中，P-V强烈抑制PC的生长(与对照组相比最多减少97%。遗传毒性和动物毒性研究表明，P-V是安全的，线粒体STAT3是其关键的分子靶点。另一方面，P-A是EGFR激活的强有力的抑制剂，与对照组相比，P-A使PC异种移植的生长减少78%。值得注意的是，当P-A和P-V联合给药时，在Kras激活的小鼠中，P-A和P-V阻止了95%的胰腺癌的发展(p&lt；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。特别强调了线粒体STAT3和EGFR信号的参与，它们在胰腺癌的发生中是必不可少的，是P-V和P-A的靶点。我们的假设是，P-V/P-A组合在预防PC方面是有效的，在线粒体STAT3和EGFR通路上协同作用。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临床前模型中的疗效；目标3：确定P-V/P-A组合在体内外的作用机制。研究设计：我们的研究将涉及在多种不同但互补的PC临床前模型中对新型药物组合的安全性、代谢率、药代动力学和有效性的评估，以及对这种新型药物组合的作用机制的评估。癌症相关性：在这些研究完成后，我们希望确定一种有前景的抗PC新药组合的关键药理学参数。鉴于缺乏有效的抗PC药物，我们认为拟议的工作有望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.