GSTP1-induced S-glutathionylation in lung cancer

肺癌中 GSTP1 诱导的 S-谷胱甘肽化

基本信息

批准号：
9922235
负责人：
Adrianus (Jos)L.J. Van der Velden
金额：
$ 35.69万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922235
关键词：
A549 Address Adenocarcinoma Adenocarcinoma Cell Adenoviruses Attenuated Biological Biological Process Biology Biopsy Cancer Etiology Cancer cell line Cell Line Cells Cessation of life Colon Carcinoma Cysteine Data Diagnosis Doxycycline Drug Targeting Enrollment Enterobacteria phage P1 Cre recombinase Enzymes Epithelial Epithelial Cells Epithelium Evaluation Exposure to Foundations Genes Glutathione Glutathione S-Transferase Glutathione S-Transferase P Glycolysis Goals Growth and Development function Hematologic Neoplasms Human Individual Intervention Isoenzymes KRAS2 gene Lead Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Medical Metabolic Modeling Molecular Conformation Mus Mutation Oral Oxidants Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Patients Pharmacology Physiological Post-Translational Protein Processing Primary Neoplasm Process Production Protein S Proteins Pyruvate Kinase Reaction Recombinants Resected Role Safety Sampling Signal Transduction Survival Rate System Testing Tissues Tracheal Epithelium Transgenic Mice Tumor Burden Tumor Tissue Tumor-Derived United States Universities Vermont Warburg Effect Work Xenograft Model Xenograft procedure aerobic glycolysis airway epithelium base cancer cell cell growth clinical application clinical investigation glutaredoxin high risk inhibitor/antagonist lung tumorigenesis malignant breast neoplasm migration mortality mouse model mutational status neoplastic cell novel outcome forecast overexpression oxidation penicillamine-glutathione mixed disulfide phase II trial response targeted treatment treatment strategy tumor tumor growth tumor xenograft tumorigenesis

项目摘要

PROJECT SUMMARY Lung cancer is the most lethal of any of the common cancers. Targeted therapy has a demonstrated benefit in the treatment of lung cancer so identifying novel druggable pathways is a priority. Glutathione S- transferase P1 (GSTP1) is an enzyme that catalyzes the post-translational modification, protein S- glutathionylation. Our preliminary data indicate that 1) GSTP1 over-expression and increased protein S- glutathionylation occurs in approximately 40% of human resected lung adenocarcinomas and is associated with a worse prognosis for early lung cancers; 2) GSTP1-induced S-glutathionylation is important for glycolysis and tumorigenesis in our models of lung adenocarcinoma, and pharmacological GSTP1 inhibition results in decreased tumor formation; and 3) GSTP1-induced S-glutathionylation controls pyruvate kinase M2 (PKM2) conformation. GSTP1 expression is strongly associated with a worse prognosis with a potential ability to identify high-risk individuals who may benefit from targeted treatment strategies. TLK199 is an orally available agent and has an excellent safety profile in Phase II trials (for hematologic cancers). This proposal will focus on addressing the mechanisms of GSTP1-induced S-glutathionylation and its role in tumorigenesis and evaluating the potential for GSTP1 targeted therapies. The hypothesis: S- glutathionylation (notably of PKM2) driven by GSTP1 is important in increasing glycolysis during lung tumorigenesis. Ways to attenuate or reverse S-glutathionylation are thus anticipated to decrease glycolysis and to disrupt tumor cell growth and will be tested in 3 specific aims. In Aim 1 we will determine the impact of inhibition of S-glutathionylation or its reversal on KRASG12D-induced tumorigenesis in an inducible lung cancer mouse model and evaluate the effect of TLK199 on tumor development and growth. This system will also allow us to identify further downstream metabolic effects and targets of GSTP1-induced protein S- glutathionylation. Aim 2 will address the importance of pyruvate kinase M2 in KRASG12D-induced tumorigenesis and investigate the impact of GSTP-linked PKM2 glutathionylation. The goal of Aim 3 is to evaluate GSTP1, overall S-glutathionylation and PKM2 in adenocarcinoma and in primary adenocarcinoma-generated patient-derived tumor xenograft (PDX) mice. We will establish PDX mice from lung cancer biopsies from our actively enrolling lung cancer study at the University of Vermont and the effects of pharmacological inhibition of GSTP on primary tumor cell and PDX mice will be evaluated. Completion of the Aims of this proposed work may prove foundational for clinical investigation of the GSTP1 inhibitor TLK199 for treatment of lung cancer.

项目摘要肺癌是任何常见癌症中最致命的。有针对性的疗法已证明有益在治疗肺癌中，因此确定新颖的可毒途径是优先的。谷胱甘肽s- 转移酶P1（GSTP1）是一种酶，可催化翻译后修饰，蛋白质S- 谷胱甘肽化。我们的初步数据表明1）GSTP1过表达和蛋白质S-的增加大约40％的人类切除的肺腺癌发生谷胱甘肽，并与之相关早期肺癌的预后较差； 2）GSTP1诱导的S-谷胱甘肽化对我们的肺腺癌模型和药理学GSTP1抑制作用中的糖酵解和肿瘤发生导致肿瘤形成减少； 3）GSTP1诱导的S-甲基二硫基因控制丙酮酸激酶 M2（PKM2）构象。 GSTP1表达与较差的预后密切相关，潜力能够识别可能从有针对性的治疗策略中受益的高风险个人。 TLK199是一个口服代理，在II期试验中具有出色的安全性（用于血液学癌症）。这提案将着重于解决GSTP1诱导的S-谷胱甘肽化的机制及其在肿瘤发生并评估GSTP1靶向疗法的潜力。假设：s- 由GSTP1驱动的谷胱甘肽化（尤其是PKM2）对于增加肺部糖酵解很重要肿瘤发生。因此，预计衰减或反向S-谷胱甘肽的方法将减少糖酵解并破坏肿瘤细胞的生长，并将以3个特定目的进行测试。在AIM 1中，我们将确定影响抑制S-谷胱甘肽的抑制作用或其对诱导肺中KRASG12D诱导的肿瘤发生的逆转癌症小鼠模型并评估TLK199对肿瘤发育和生长的影响。这个系统还将使我们能够确定GSTP1诱导蛋白S-的进一步下游代谢作用和靶标谷胱甘肽化。 AIM 2将解决丙酮酸激酶M2在KRASG12D引起的重要性肿瘤发生并研究GSTP连接的PKM2谷胱甘肽的影响。目标3的目标是评估腺癌中的GSTP1，总体S-谷二硫代化和PKM2和原发性的PKM2 腺癌生成的患者衍生的肿瘤异种移植（PDX）小鼠。我们将从我们在佛蒙特大学积极入学的肺癌研究中的肺癌活检和将评估GSTP药理抑制对原发性肿瘤细胞和PDX小鼠的影响。完成这项拟议工作的目的的完成可能证明是对临床研究的基础 GSTP1抑制剂TLK199治疗肺癌。