GSTP1-induced S-glutathionylation in lung cancer

项目总结 肺癌是所有常见癌症中最致命的。靶向治疗有明显的益处。 因此，在肺癌的治疗中，确定新的可用药途径是当务之急。谷胱甘肽S 转移酶P_1是一种催化翻译后修饰的酶，蛋白S- 谷胱甘肽基化。我们的初步数据表明：1)GSTP1过表达并增加了S的蛋白- 大约40%的人切除的肺腺癌中存在谷胱甘肽基化，并与 早期肺癌预后较差；2)谷胱甘肽转移酶1诱导的S谷胱甘肽活化在肺癌发生发展中起重要作用。 我们的肺腺癌模型中的糖酵解和肿瘤发生，以及药物对GSTP1的抑制 结果减少肿瘤的形成；和3)谷胱甘肽转移酶1诱导的S谷胱甘肽控制丙酮酸激酶 M2(PKM2)构象。GSTP1的表达与预后较差密切相关 识别可能受益于靶向治疗策略的高危个体的能力。TLK199是一款 该药是一种口服制剂，在II期试验(用于血液病)中具有极好的安全性。这 提案将侧重于研究谷胱甘肽转移酶1诱导的S谷胱甘肽基化的机制及其在 肿瘤发生和评估GSTP1靶向治疗的可能性。假设：S-- GSTP1驱动的谷胱甘肽基化(尤其是PKM2)在增加肺内糖酵解中起重要作用 肿瘤发生学。因此，减弱或逆转S谷胱甘肽基化的方法有望减少糖酵解。 和干扰肿瘤细胞的生长，并将在3个特定的目标进行测试。在目标1中，我们将确定影响 S谷胱甘肽抑制或逆转KrasG12D诱导的小鼠肺肿瘤发生 建立小鼠肿瘤模型，评价TLK199对肿瘤生长发育的影响。这个系统 这也将使我们能够进一步确定GSTP1诱导蛋白S的下游代谢效应和靶点- 谷胱甘肽基化。目标2将阐述丙酮酸激酶M2在KrasG12D诱导中的重要性 肿瘤发生和研究GSTP连接的PKM2谷胱甘肽基化的影响。目标3的目标是 腺癌与原发癌GSTP_1、总S-谷胱甘肽和蛋白激酶M_2的比较 腺癌患者来源的肿瘤异种移植(PDX)小鼠。我们将建立PDX小鼠 来自我们在佛蒙特州大学的肺癌研究的肺癌活检 将评估GSTP对原代肿瘤细胞和PDX小鼠的药理抑制作用。 这项拟议工作的目标的完成可能被证明是临床研究的基础 GSTP1抑制剂TLK199用于治疗肺癌。

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.