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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：
10159874
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159874
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 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 K-ras mouse model KRAS2 gene KRASG12D 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 Prognosis 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 cell growth clinical application clinical investigation glutaredoxin high risk inhibitor/antagonist lung cancer cell lung tumorigenesis malignant breast neoplasm migration mortality mouse model mutational status neoplastic cell novel 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.

项目概要肺癌是所有常见癌症中最致命的。靶向治疗已被证实具有益处在肺癌的治疗中，确定新的药物途径是当务之急。谷胱甘肽S- 转移酶 P1 (GSTP1) 是一种催化翻译后修饰的酶，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-增加大约 40% 的人类切除肺腺癌中发生谷胱甘肽化，并且与早期肺癌的预后较差； 2) GSTP1诱导的S-谷胱甘肽化对于我们的肺腺癌模型中的糖酵解和肿瘤发生以及药理学 GSTP1 抑制导致肿瘤形成减少； 3) GSTP1 诱导的 S-谷胱甘肽化控制丙酮酸激酶 M2 (PKM2) 构象。 GSTP1 表达与较差的预后密切相关，并具有潜在的潜在风险能够识别可能受益于针对性治疗策略的高风险个体。 TLK199 是一个口服药物，在 II 期试验（针对血液癌症）中具有出色的安全性。这该提案将重点关注 GSTP1 诱导的 S-谷胱甘肽化的机制及其在肿瘤发生并评估 GSTP1 靶向治疗的潜力。假设：S- GSTP1 驱动的谷胱甘肽化（尤其是 PKM2）对于增加肺期间的糖酵解非常重要肿瘤发生。因此，减弱或逆转 S-谷胱甘肽化的方法有望减少糖酵解并破坏肿瘤细胞生长，并将在 3 个具体目标中进行测试。在目标 1 中，我们将确定影响 S-谷胱甘肽化的抑制或其逆转对 KRASG12D 诱导的肺肿瘤发生的影响癌症小鼠模型并评估 TLK199 对肿瘤发生和生长的影响。这个系统还将使我们能够进一步确定 GSTP1 诱导的蛋白 S- 的下游代谢效应和靶标谷胱甘肽化。目标 2 将解决丙酮酸激酶 M2 在 KRASG12D 诱导中的重要性肿瘤发生并研究 GSTP 连接的 PKM2 谷胱甘肽化的影响。目标 3 的目标是评估腺癌和原发性肿瘤中的 GSTP1、总体 S-谷胱甘肽化和 PKM2 腺癌产生的患者来源的肿瘤异种移植（PDX）小鼠。我们将建立 PDX 小鼠肺癌活检来自我们在佛蒙特大学积极招募的肺癌研究和将评估GSTP对原发性肿瘤细胞和PDX小鼠的药理抑制作用。完成这项拟议工作的目标可能会为该药物的临床研究奠定基础。 GSTP1抑制剂TLK199用于治疗肺癌。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lung organoids: advances in generation and 3D-visualization.

DOI：
10.1007/s00418-020-01955-w
发表时间：
2021-03
期刊：
Histochemistry and cell biology
影响因子：
2.3
作者：
Cunniff B;Druso JE;van der Velden JL
通讯作者：
van der Velden JL

Loss of RUNX1 is associated with aggressive lung adenocarcinomas.

DOI：
10.1002/jcp.26201
发表时间：
2018-04
期刊：
Journal of cellular physiology
影响因子：
5.6
作者：
Ramsey J;Butnor K;Peng Z;Leclair T;van der Velden J;Stein G;Lian J;Kinsey CM
通讯作者：
Kinsey CM