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: 10631142
• 负责人: HAIAN FU
• 金额: $ 39.01万
• 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/10631142
• 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; Immunocompetent; Immunologics; Immunosuppression; Immunotherapy; In Vitro; 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; Phase; Phenotype; Program Research Project Grants; Regulation; Regulator Genes; Reporting; Resistance; Role; STAT1 protein; STK11 gene; Sampling; Signal Transduction; Stimulator of Interferon Genes; Subgroup; TBK1 gene; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tumor Immunity; Tumor Tissue; antagonist; anti-cancer; cIAP1 protein; cancer infiltrating T cells; cancer therapy; cell killing; design; effective therapy; gene repression; immune cell infiltrate; improved; in vivo; inhibitor; inhibitor-of-apoptosis protein; molecular targeted therapies; mouse model; mutant; mutant mouse model; novel therapeutic intervention; pharmacologic; 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.

总结 Emory肺癌P01申请的项目2重点关注抑制的抗癌药物的解剖 LKB 1突变的肺腺癌（LUAD）中涉及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。而 分子靶向疗法在具有确定的突变如EGFR和ALK中的那些突变的患者中是有效的， 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 刺激宿主免疫系统摧毁肿瘤的疗法。不幸的是，大多数肺癌 患者对这些ICI的反应较差。特别是，具有LKB 1突变的LUAD患者没有靶向 治疗，对ICI无反应。因此，迫切需要了解这种肿瘤免疫相互作用， LKB 1突变型LUAD，并开发新的治疗方法来克服免疫治疗耐药性。它 LKB 1突变型LUAD的免疫抑制状态似乎与LKB 1突变型LUAD的沉默STimulator相关。 干扰素基因（STING），一种调节先天免疫的细胞溶质DNA传感器。因此，扭转战略 STING表达可以重新建立肿瘤免疫微环境，并重新使肿瘤对有效的免疫应答敏感。 用STING激动剂或ICI治疗。我们发现抑制剂的小分子拮抗剂birinapant 凋亡蛋白（IAP），可以恢复STING表达，重新激活STING信号传导，并增强免疫功能。 LKB 1-mut LUAD细胞的效应细胞杀伤。为了进一步支持这一修改后的应用程序，我们的新数据显示， birinapant在免疫活性细胞中选择性地表现出有效的体内免疫依赖性抗肿瘤活性， LKB 1突变小鼠模型。这些结果导致了我们的中心假设，即LKB 1缺失与STING相关 通过异常IAP功能下调，使用IAP抑制剂的药理学靶向可能会恢复 STING在LKB 1-mut LUAD中的表达和重建免疫应答途径，用于增强治疗 功效为了验证这一假设，我们建议使用来自肿瘤组织的细胞、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 LKB 1-mut LUAD细胞中STING的表达; 2）确定IAP抑制剂和STING的治疗效果 LKB 1-mut肿瘤中的激动剂;和3）评估IAP抑制剂与 LKB 1-mut肿瘤中的PD-1阻断剂。我们将在以下背景下审查IAP-STING轴的影响： GDH 1（项目1）和FAK超活化（项目3），以提高对LKB 1免疫机制的理解 响应信号。为了实现该提案的目标，我们的目标是提供使用IAP的临床前证据 抑制剂，如birinapant，单独或与STING激动剂或ICI组合治疗肺癌患者 LKB 1基因突变