Estrogen receptors restrict tumor-promoting inflammation in K-ras mutant lung cancer

雌激素受体限制 K-ras 突变肺癌中促肿瘤的炎症

• 批准号: 10386921
• 负责人: Michael Joseph Clowers
• 金额: $ 3.42万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386921
• 关键词: Bone Marrow Transplantation; Cancer Etiology; Cells; Cessation of life; Clinical Trials; DNA Sequence Alteration; Development; Epithelial; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Female; Genes; Genetic; Genotype; Goals; Gonadal Steroid Hormones; Immune; Immunotherapy; Infiltration; Inflammation; Inflammatory; Interleukin-6; KRAS2 gene; Knock-out; Light; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Modality; Modeling; Mus; Mutant Strains Mice; Mutate; Mutation; Myelogenous; Myeloid Cells; Nuclear Hormone Receptors; Outcome; Pathway interactions; Patients; Phenotype; Play; Production; Protein Isoforms; Rattus; Receptor Gene; Receptor Signaling; Risk; Role; STAT3 gene; Signal Transduction; Smoker; Structure of parenchyma of lung; System; Testing; Tumor Burden; Tumor Immunity; Tumor-infiltrating immune cells; United States; Viral Oncogene; base; cancer clinical trial; cancer type; carcinogenesis; cell type; cigarette smoke; driver mutation; druggable target; female sex hormone; individualized medicine; inhibitor; interest; male; men; mutant; neoplastic cell; novel therapeutics; personalized medicine; promoter; receptor binding; recruit; resistance mechanism; resistance mutation; sarcoma; sex; sex disparity; single-cell RNA sequencing; targeted treatment; transcription factor; tumor; tumor microenvironment; tumorigenesis

Abstract More patients die from lung cancer than from any other cancer type each year in the United States. Moreover, lung cancers with K-ras driver mutations are resistant to targeted therapies. Therefore, there is an unmet need to find druggable targets downstream of K-ras. Tumor-promoting inflammation occurs frequently as a result of K-ras mutations that activate the NF-κB pathway, the production of interleukin 6, and activation of its downstream transcription factor STAT3. However, when we knock out STAT3 in tumor cells in mice, females have fewer tumors, but males have more. This sex disparity is driven by overactivation of NF-κB in males, but in females, estrogen signaling reduces NF-κB and tumor-promoting inflammation. This protective phenotype requires estrogen receptors (ERs), nuclear hormone receptors that bind estrogen and interact with NF-κB. There are two genes for ERs: ERα and ERβ. ERβ is the major ER isoform expressed in lung tissue, and ERα is mainly in immune cells. Accordingly, I hypothesize that in the absence of STAT3 in the lung epithelium, ERα and ERβ signaling is protective in K-ras mutant lung cancer by inhibiting NF-κB-driven pro-tumor inflammation. I have two specific aims to test this hypothesis, one aim for each of the cellular compartments of interest: tumor cells and myeloid cells. Aim 1: I will knock out ERβ in tumors to determine if it is required for cancer protection in females. Aim 2: since ERα predominates in tumor-infiltrating myeloid immune cells, I will knock out ERα in myeloid cells to determine if it is also required for cancer protection. Successful completion of these aims will further explain the mechanism of ER-dependent lung cancer protection, with potential for estrogen and ERα/ERβ to play a novel therapeutic role. Since clinical trials for STAT3 inhibitors have begun, it is important to understand the sex- specific outcomes of targeting STAT3. Our results will guide clinicians to better personalize therapy by taking sex hormones into account when treating patients. They will also shed light on the mechanism of resistance to currently available immunotherapies and provide alternative modalities.

抽象的 在美国，死于肺癌的患者比每年其他任何其他癌症类型都要多。而且， 具有K-RAS驱动突变的肺癌对靶向疗法具有抗性。因此，有未满足的需求 在K-Ras的下游找到可吸毒的靶标。促肿瘤炎症经常发生 激活NF-κB途径的K-RAS突变，白介素6的产生及其下游激活 转录因子Stat3。但是，当我们在小鼠的肿瘤细胞中淘汰STAT3时，女性的较少 肿瘤，但男性还有更多。这种性别差异是由男性NF-κB过度激活所驱动的，但在女性中， 雌激素信号传导减少NF-κB和促进肿瘤的注射。这种受保护的表型需要 雌激素受体（ERS），结合雌激素并与NF-κB相互作用的核马酮受体。有两个 ERS的基因：ERα和ERβ。 ERβ是在肺组织中表达的主要ER同工型，ERα主要在 免疫细胞。根据，我假设在肺上皮中没有STAT3的情况下，ERα和ERβ 通过抑制NF-κB驱动的促肿瘤注射，在K-RAS突变肺癌中受到信号传导。我有两个 特定的目的是检验这一假设，一个目标是感兴趣的每个细胞室的目的：肿瘤细胞和 髓样细胞。目标1：我将在肿瘤中敲出ERβ，以确定女性癌症保护是否需要。 AIM 2：由于ERα在肿瘤浸润的髓样免疫球中占主导 确定癌症保护是否也需要。这些目标的成功完成将进一步解释 ER依赖性肺癌保护的机制，具有雌激素和ERα/ERβ的潜力 治疗作用。由于STAT3抑制剂的临床试验已经开始，因此了解性别很重要 - 靶向STAT3的具体结果。我们的结果将指导临床医生通过服用来更好地个性化治疗 治疗患者时要考虑性骑士。他们还将阐明抵抗的机制 当前可用的免疫疗法并提供替代方式。