Project 2: Reversing STING-mediated immunosuppression in LKB1-mutant lung adenocarcinoma

项目 2：逆转 LKB1 突变型肺腺癌中 STING 介导的免疫抑制

• 批准号: 10411667
• 负责人: HAIAN FU
• 金额: $ 39.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411667
• 关键词: Adenocarcinoma Cell; Agonist; Bioinformatics; Biometry; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; DNA; Data; Databases; Dissection; Down-Regulation; Effector Cell; Epidermal Growth Factor Receptor; Exhibits; Gene Activation; Gene Expression; Genetically Engineered Mouse; Goals; IRF3 gene; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunocompetent; Immunologics; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Interferon Type I; Intrinsic factor; Isogenic transplantation; JAK1 gene; Leadership; Lung Adenocarcinoma; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Natural Immunity; Non-Small-Cell Lung Carcinoma; PD-1 blockade; PTK2 gene; Pathway interactions; Patients; Pharmacology; Phase; Phenotype; Program Research Project Grants; Regulation; Regulator Genes; Reporting; Resistance; Role; STAT1 protein; STK11 gene; Sampling; Signal Transduction; Stimulator of Interferon Genes; Subgroup; T-Lymphocyte; TBK1 gene; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tumor Immunity; Tumor Tissue; Tumor-infiltrating immune cells; antagonist; anti-cancer; cIAP1 protein; cancer therapy; cell killing; design; effective therapy; improved; in vivo; inhibitor-of-apoptosis protein; molecular targeted therapies; mutant; mutant mouse model; novel therapeutic intervention; pre-clinical; protein function; protein protein interaction; research clinical testing; response; restoration; sample archive; screening; sensor; small molecule; standard care; targeted treatment; therapeutically effective; transplant model; tumor; tumor progression; tumor-immune system interactions; tumorigenesis

SUMMARY Project 2 of the Emory Lung Cancer P01 application focuses on the dissection of suppressed anticancer immunity mechanisms involving STING in lung adenocarcinoma (LUAD) with LKB1 mutations for translational gains. Lung cancer is the leading cause of cancer death in the US with limited therapeutic options. While molecularly targeted therapies are effective in patients with defined mutations such as those in EGFR and ALK, immune checkpoint inhibitors (ICI) have brought hope for additional patients and have revolutionized cancer therapy to stimulate the host immune system to destroy tumors. Unfortunately, the majority of lung cancer patients show poor response to such ICIs. In particular, LUAD patients with LKB1 mutations have no targeted therapies and are unresponsive to ICIs. Thus it is urgent to understand the tumor-immune interactions in such LKB1-mutant LUAD and develop new therapeutic approaches to overcome immunotherapy resistance. It appears that the immune suppressed state of LKB1-mutant LUAD is associated with the silenced STimulator of INterferon Gene (STING), a cytosolic DNA sensor that regulates innate immunity. Thus, strategies to reverse STING expression may re-establish the tumor-immune microenvironment and re-sensitize tumors for effective treatment with STING agonists or ICIs. We discovered that birinapant, a small molecule antagonist of Inhibitor of Apoptosis Protein (IAP), can restore STING expression, reactivate STING signaling, and enhance immune effector cell killing of LKB1-mut LUAD cells. In further support of this revised application, our new data showed that birinapant exhibited potent in vivo immune-dependent anti-tumor activity selectively in immune competent LKB1-mutant mouse model. These results led to our central hypothesis that LKB1 loss is associated with STING downregulation through aberrant IAP functions, and pharmacological targeting using IAP inhibitors may restore STING expression and re-establish immune response pathways in LKB1-mut LUAD for enhanced therapeutic efficacy. To test this hypothesis, we propose to use a combination of cell, mouse, and patient tumor tissues from Core 2 and Project 3 clinical trials 1) to examine the molecular mechanisms by which IAP inhibitors induce STING expression in LKB1-mut LUAD cells; 2) to determine the therapeutic effect of IAP inhibitors and STING agonists in LKB1-mut tumors; and 3) to evaluate the therapeutic effect of IAP inhibitors in combination with a PD-1 blockade agent in LKB1-mut tumors. We will examine the impact of the IAP-STING axis in the context of GDH1 (Project 1) and FAK hyperactivation (Project 3) to improve mechanistic understanding of LKB1 immune response signaling. Accomplishing the goals of the proposal, we aim to deliver preclinical evidence for using IAP inhibitors, such as birinapant, alone or in combination with STING agonists or ICI to treat lung cancer patients with LKB1 alterations.

概括 埃默里肺癌P01申请项目2专注于解析抑制性抗癌药物 涉及 LKB1 翻译突变的肺腺癌 (LUAD) 中 STING 的免疫机制 收益。肺癌是美国癌症死亡的主要原因，治疗选择有限。尽管 分子靶向治疗对于具有特定突变（例如 EGFR 和 ALK 突变）的患者有效， 免疫检查点抑制剂（ICI）为更多患者带来了希望，并彻底改变了癌症 刺激宿主免疫系统破坏肿瘤的疗法。不幸的是，大多数肺癌 患者对此类 ICI 的反应较差。特别是，LKB1突变的LUAD患者没有针对性的治疗方法。 治疗且对 ICI 没有反应。因此，迫切需要了解肿瘤与免疫的相互作用。 LKB1 突变 LUAD 并开发新的治疗方法来克服免疫治疗耐药性。它 看来 LKB1 突变体 LUAD 的免疫抑制状态与 STimulator 的沉默有关 干扰素基因 (STING)，一种调节先天免疫的胞质 DNA 传感器。因此，扭转策略 STING 表达可能会重建肿瘤免疫微环境，并使肿瘤重新敏感，以有效发挥作用 使用 STING 激动剂或 ICI 治疗。我们发现 birinapant，一种抑制剂的小分子拮抗剂 凋亡蛋白 (IAP)，可以恢复 STING 表达，重新激活 STING 信号传导，增强免疫 LKB1-mut LUAD 细胞的效应细胞杀伤。为了进一步支持这一修订后的申请，我们的新数据显示 birinapant 在免疫活性中选择性地表现出有效的体内免疫依赖性抗肿瘤活性 LKB1突变小鼠模型。这些结果得出我们的中心假设：LKB1 丢失与 STING 相关 通过异常的 IAP 功能下调，使用 IAP 抑制剂的药理学靶向可能会恢复 LKB1-mut LUAD 中的 STING 表达并重建免疫反应途径以增强治疗效果 功效。为了检验这一假设，我们建议使用细胞、小鼠和患者肿瘤组织的组合 核心 2 和项目 3 临床试验 1) 检查 IAP 抑制剂诱导的分子机制 LKB1-mut LUAD 细胞中的 STING 表达； 2）确定IAP抑制剂和STING的治疗效果 LKB1-mut 肿瘤中的激动剂； 3) 评估 IAP 抑制剂联合药物的治疗效果 LKB1 突变肿瘤中的 PD-1 阻断剂。我们将在以下背景下研究 IAP-STING 轴的影响： GDH1（项目 1）和 FAK 过度激活（项目 3）可提高对 LKB1 免疫机制的理解 响应信号。为了实现提案的目标，我们的目标是提供使用 IAP 的临床前证据 抑制剂，例如 birinapant，单独或与 STING 激动剂或 ICI 联合治疗肺癌患者 与 LKB1 的改变。