GSTP1-induced S-glutathionylation in lung cancer

项目摘要 肺癌是所有常见癌症中最致命的。靶向治疗具有已证实的益处 在肺癌的治疗中，识别新的药物途径是一个优先事项。谷氨酸S- 转移酶P1（GSTP 1）是催化翻译后修饰的酶，蛋白S- 谷胱甘肽化我们的初步数据表明：1）GST 1过表达和增加蛋白S- 谷胱甘肽化发生在大约40%的人类切除的肺腺癌中，并且与 早期肺癌预后较差; 2）GSTP 1诱导的S-谷胱甘肽化对于 糖酵解和我们的肺腺癌模型中的肿瘤发生，以及药物GSTP 1抑制 导致肿瘤形成减少;和3）GST 1诱导的S-谷胱甘肽化控制丙酮酸激酶 M2（PKM 2）构象。GSTP 1表达与预后不良密切相关， 识别可能从有针对性的治疗策略中受益的高危个体的能力。TLK 199是一种 在II期临床试验（用于血液癌症）中具有极好的安全性。这 该提案将集中于解决GSTP 1诱导的S-谷胱甘肽化的机制及其在 肿瘤发生和评估GST P1靶向治疗的潜力。假设：S- 由GST 1驱动的谷胱甘肽化（特别是PKM 2）在肺内增加糖酵解中很重要。 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个特定目标中进行测试。在目标1中，我们将确定 在诱导型肺中抑制S-谷胱甘肽化或逆转其对KRASG 12 D诱导的肿瘤发生的作用 肿瘤小鼠模型，并评估TLK 199对肿瘤发展和生长的影响。该系统 也将使我们能够确定进一步的下游代谢效应和GST P1诱导的蛋白S- 谷胱甘肽化目的2将阐述丙酮酸激酶M2在KRASG 12 D诱导的细胞凋亡中的重要性。 肿瘤发生和研究GST连接的PKM 2谷胱甘肽化的影响。目标3的目标是 评估腺癌和原发性肝癌中的GST 1、总体S-谷胱甘肽化和PKM 2 腺癌产生的患者来源的肿瘤异种移植物（PDX）小鼠。我们将建立PDX小鼠， 来自佛蒙特大学积极招募的肺癌研究的肺癌活检和 评价GSTP对原发肿瘤细胞和PDX小鼠的药理学抑制作用。 完成这项拟议工作的目的可能是临床研究的基础。 用于治疗肺癌的GST P1抑制剂TLK 199。

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.