Phospho-sulindac for Lung Cancer Treatment

磷酸舒林酸用于肺癌治疗

基本信息

批准号：
8895867
负责人：
Basil Rigas
金额：
$ 32.79万
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：
2014
资助国家：
美国
起止时间：
2014-07-22 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895867
关键词：
Adverse effects Age Animal Model Animals Anions Antioxidants Apoptosis Biological Markers Butane Cancer Etiology Cell Cycle Cell Cycle Progression Cell Line Cells Cessation of life Chemicals Cysteine Data Detection Development Disease Dose Drug Combinations Epidermal Growth Factor Receptor Equilibrium Free Radicals Genes Genetic Glutathione Growth Health Human In Vitro Incidence KRAS2 gene Lead Link Lung Lung Neoplasms MAP Kinase Gene MAPK8 gene Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Mediating Modeling Molecular Target Mus Mutation NADPH Oxidase Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Non-Steroidal Anti-Inflammatory Agents Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Oxygen PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Reactive Oxygen Species Safety Side Signal Pathway Signal Transduction Staging Stress Sulindac Superoxide Dismutase Superoxides Survival Rate System Therapeutic Therapeutic Index Thioredoxin Transgenic Model Wit Work Xenograft procedure base cancer cell cancer therapy design drug efficacy in vivo member nanocarrier novel outcome forecast peroxiredoxin response tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths, with a 5-year survival rate of <15%. This alarming prognosis makes clear the urgent need for new efficacious agents for its treatment. Phospho-sulindac (PS), a novel compound developed by us, inhibits the growth of lung cancer xenografts by 87-103%, eliminating, in one study, 3/7 lung cancer tumors. In addition to its remarkable efficacy, PS has an exceptional safety profile. Thus PS has a strong potential of becoming an efficacious agent for the treatment of lung cancer. Our preliminary data indicate that the mechanism of the anti-cancer effect of PS is, in its essence, the following: PS induces oxidative stress, which activates redox-sensitive signaling cascades, which in turn block cell cycle progression, inhibit proliferation and induce apoptosis; the end result is inhibition of tumor growth. The development of oxidative stress by PS is due to: a) activation of NADPH oxidase, which generates the free radical superoxide anion; and b) suppression of several members of the antioxidant system of the cell, both enzymatic (the thioredoxin system, peroxiredoxin, cytoglobin, superoxide dismutase) and chemical (glutathione).These effects increase rapidly the cellular levels of reactive oxygen species (ROS) shifting the redox balance towards oxidative stress. In vivo, co-administration of the antioxidant N-acetyl-cysteine and PS suppresses oxidative stress and eliminates the anticancer effect of PS on lung cancer xenografts. Our hypothesis is that PS is a highly effective and safe agent for the treatment of lung cancer acting predominantly by inducing oxidative stress. To evaluate this hypothesis, we propose the following specific aims: 1) Assess the efficacy of PS against lung cancer in animal tumor models: We will expand the efficacy studies to include xenografts of additional cell lines mirroring the genetic subtypes of lung cancer and a transgenic model of lung cancer. 2) Validate efficacy results in patient-derived lung cancer xenografts. They provide excellent prediction of drug efficacy in humans; we will study tumors with KRAS or EGFR mutations. And 3) Study in vitro and in vivo the molecular targets involved in the induction of oxidative stress by PS and the downstream signaling pathways that mediate its anticancer effect. We will evaluate the main contributors to oxidative stress and signaling pathways downstream of oxidative stress.

描述（申请人提供）：肺癌是癌症死亡的主要原因，5年生存率<15%。这种令人震惊的预后表明迫切需要新的有效药物来治疗该病。磷酸舒林酸 (PS) 是我们开发的一种新型化合物，可抑制肺癌异种移植物的生长 87-103%，在一项研究中消除了 3/7 的肺癌肿瘤。除了其卓越的功效外，PS 还具有卓越的安全性。因此PS具有成为治疗肺癌的有效药物的强大潜力。我们的初步数据表明，PS的抗癌作用机制是：本质上，PS 会诱导氧化应激，从而激活氧化还原敏感的信号级联，进而阻止细胞周期进程、抑制增殖并诱导细胞凋亡；最终结果是抑制肿瘤生长。 PS 产生氧化应激的原因是： a) NADPH 氧化酶的激活，产生自由基超氧阴离子； b) 抑制细胞抗氧化系统的多个成员，包括酶（硫氧还蛋白系统、过氧化氧还蛋白、细胞珠蛋白、超氧化物歧化酶）和化学（谷胱甘肽）。这些作用迅速增加活性氧 (ROS) 转移的细胞水平针对氧化应激的氧化还原平衡。在体内，抗氧化剂 N-乙酰半胱氨酸和 PS 的共同给药可抑制氧化应激并消除 PS 对肺癌异种移植物的抗癌作用。我们的假设是，PS 是一种高效且安全的肺癌治疗药物，主要通过诱导氧化应激发挥作用。为了评估这一假设，我们提出以下具体目标： 1) 评估 PS 在动物肿瘤模型中对抗肺癌的功效：我们将扩大功效研究，以包括反映肺癌遗传亚型的其他细胞系的异种移植物和转基因肺癌模型。 2) 验证患者来源的肺癌异种移植物的疗效结果。它们可以很好地预测药物在人体中的功效；我们将研究具有 KRAS 或 EGFR 突变的肿瘤。 3）体外和体内研究参与PS诱导氧化应激的分子靶点以及介导其抗癌作用的下游信号通路。我们将评估氧化应激的主要贡献者和氧化应激下游的信号通路。