Phospho-sulindac for Lung Cancer Treatment

磷酸舒林酸用于肺癌治疗

基本信息

批准号：
9754402
负责人：
Basil Rigas
金额：
$ 6.72万
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：
2018
资助国家：
美国
起止时间：
2018-11-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754402
关键词：
Address Animal Model Animals Antineoplastic Agents Antioxidants Apoptosis Biological Markers Butane Cancer Etiology Cell Cycle Progression Cell Line Cells Cessation of life Chemicals Clinical Cysteine Data Development Diagnosis Disease Dose Drug Combinations Early Diagnosis Early treatment Epidermal Growth Factor Receptor Equilibrium F2-Isoprostanes Free Radicals Genetic Glutathione Growth Human In Vitro Incidence Intravenous KRAS2 gene Lead Link Lung Neoplasms MAP Kinase Gene MAPK8 gene Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Maximum Tolerated Dose 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 PTEN gene Patients Pre-Clinical Model Reactive Oxygen Species Safety Signal Pathway Signal Transduction Sulindac Superoxide Dismutase Superoxides Survival Rate System TXN gene Therapeutic Agents Therapeutic Effect Therapeutic Index Transgenic Model Work Xenograft procedure anti-cancer base cancer cell cancer therapy design dityrosine drug efficacy efficacy study in vivo lung cancer prevention lung small cell carcinoma member nanocarrier novel outcome forecast peroxiredoxin response side effect subcutaneous tumor tumor growth

项目摘要

ABSTRACT 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.

抽象的肺癌是癌症死亡的主要原因，5年生存率<15％。这个令人震惊的预后清楚地表明，迫切需要对新的有效药物进行治疗。磷酸 - 苏富烷（PS），a 美国开发的新颖化合物抑制了87-103％的肺癌异种移植物的生长，消除了，在一项研究，3/7肺癌肿瘤。除了其出色的功效外，PS还具有出色的安全性。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的抗癌作用的机制在本质上是以下内容：PS 诱导氧化应激，该应激激活了氧化还原敏感的信号级联反应，从而阻止细胞周期进展，抑制增殖并诱导凋亡；最终结果是抑制肿瘤生长。这 PS通过PS开发氧化应激的原因是：a）NADPH氧化酶的激活，这会产生游离自由基超氧阴离子； b）抑制细胞抗氧化剂系统的几个成员酶促（硫氧还蛋白系统，过氧蛋白，细胞蛋白蛋白，超氧化物歧化酶）和化学物质（谷胱甘肽）。这些影响迅速增加了活性氧（ROS）的细胞水平，转移了氧化还原朝着氧化应激的平衡。在体内，抗氧化剂N-乙酰基半胱氨酸和PS的共同给药抑制氧化应激，并消除PS对肺癌异种移植物的抗癌作用。我们的假设是PS是治疗肺癌作用的高效且安全的药物主要是通过诱导氧化应激。为了评估这一假设，我们提出以下特定目的：1）评估PS对肺癌模型中PS的功效：我们将扩大功效研究包括其他细胞系的异种移植，反映了肺癌的遗传亚型和A 肺癌的转基因模型。 2）验证疗效导致患者来源的肺癌异种移植物。他们提供对人类药物疗效的极好预测；我们将研究具有KRAS或EGFR突变的肿瘤。 3）在体外和体内研究参与PS和PS诱导氧化应激的分子靶标介导其抗癌作用的下游信号通路。我们将评估主要贡献者氧化应激的氧化应激和信号通路。