Two phospho-compounds for pancreatic cancer prevention

两种用于预防胰腺癌的磷酸化合物

基本信息

批准号：
9040890
负责人：
Gerardo Guillermo Mackenzie
金额：
$ 0.85万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-26 至 2016-11-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040890
关键词：
Animals Area Aspirin BRCA2 gene Breast Cancer gene Cancer Control Cancer cell line Carcinoma Chemical Structure Chemoprevention Chemopreventive Agent Development Disease Drug Combinations Drug Kinetics Drug Targeting Electron Transport Ensure Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelium Evaluation Familial Atypical Multiple Mole Melanoma Goals Growth Hamsters Health Hereditary Breast Carcinoma Human In Vitro Individual Inherited KRAS2 gene Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Metabolism Mitochondria Modeling Molecular Target Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Pancreas Pancreatic Cyst Pancreatic Intraepithelial Neoplasia Pancreatic carcinoma Pancreatitis Parents Pathway interactions Patients Peutz-Jeghers Syndrome Play Population Pre-Clinical Model Premalignant Prevention strategy Protocols documentation Receptor Activation Receptor Signaling Recording of previous events Research Design Risk Risk Factors Role Route STAT3 gene Safety Signal Pathway Staging Survival Rate Testing Tobacco smoking Toxic effect Transgenic Organisms Tumor Volume Valproic Acid Work Xenograft Model Xenograft procedure base cancer prevention carcinogenesis chemotherapy chronic pancreatitis genetic risk factor genotoxicity high risk in vivo inhibitor/antagonist mouse model novel novel drug combination novel strategies pancreatic cancer cells pancreatic neoplasm prevent research clinical testing tumorigenesis

项目摘要

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.

描述（由适用提供）：胰腺癌（PC）是一种高度侵略性的癌症，5年生存率<5％。当前的全身标准化学疗法为患者提供了边际益处，仅延长了几周的生存。因此，开发新型PC的预防性策略具有提高重要性，而新型化学预防剂的发展是最关键的组成部分。我们建议研究两种新型药物[磷酸 - 棒状酸（P-V）和磷酸 - 阿素蛋白（P-A）]，作为PC预防的新药物组合。最近，我们表明，P-V在多种PC的临床前模型中强烈抑制PC的增长（与对照相比，降低了97％。P-V是安全的，如遗传毒性和动物毒性研究所示，线粒体STAT3是其关键分子靶标的。另一方面，P-A是EGFR Expriending in Graniely in Grancion in Gressive and Redicagration PC的强烈抑制剂，并将其与Reductation reductation reductation reductation reductation reductation reductation相比。 P-A和P-V组合在具有活化的KRA的小鼠中，胰腺癌的发展量（P <0.01）。 P-V和P-A。我们的假设是P-V/P-A组合在PC预防中有效，在线粒体STAT3和EGFR途径上进行协同作用。目标＃2：确定PC临床前模型中P-V/P-A组合的效率；目标＃3：确定P-V/P-A组合在体外和体内的作用机理。研究设计：我们的研究将涉及对新型药物组合PC的安全性，代谢，药代动力学和有效性的评估，以及PC的完整临床前模型以及对这种新药物组合的作用机理的评估。癌症相关性：完成这些研究后，我们预计将确定有望针对PC的新型药物组合的关键药物参数。鉴于缺乏针对PC的有效代理，我们认为拟议的工作具有在这一领域取得重大进步的希望。