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

基本信息

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
项目类别：
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

项目摘要

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 Emory肺癌P01应用的项目2侧重于抑制抗癌的解剖具有LKB1突变的肺腺癌（LUAD）中涉及刺激的免疫机制收益。肺癌是美国癌症死亡的主要原因，治疗选择有限。尽管分子靶向疗法对于具有定义突变的患者，例如EGFR和ALK中的患者有效免疫检查点抑制剂（ICI）给其他患者带来了希望，并彻底改变了癌症刺激宿主免疫系统破坏肿瘤的治疗。不幸的是，大多数肺癌患者对此类ICI的反应不佳。特别是，LKB1突变的LUAD患者没有针对性疗法，对ICI没有反应。因此，迫切需要理解这种肿瘤免疫相互作用 lkb1突变luAD并开发出新的治疗方法来克服免疫疗法的耐药性。它看来LKB1突变剂LUAD的免疫抑制状态与沉默的刺激器有关干扰素基因（Sting），一种调节先天免疫力的胞质DNA传感器。因此，逆转策略刺痛表达可能会重新建立肿瘤免疫微环境并重新敏感性肿瘤以有效用刺痛的激动剂或ICI治疗。我们发现Birinapant是抑制剂的小分子拮抗剂凋亡蛋白（IAP）的凋亡，可以恢复刺激表达，重新激活刺激信号并增强免疫 LKB1-MUT LUAD细胞的效应细胞杀死。为了进一步支持此修订的应用程序，我们的新数据显示该Birinapant在免疫胜任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。这些结果导致了我们的中心假设，即LKB1损失与刺有关通过异常IAP功能下调，使用IAP抑制剂的药理学靶向可能还原 LKB1-MUT LUAD中的刺激表达和重建免疫反应途径，以增强治疗功效。为了检验这一假设，我们建议将细胞，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细胞中的刺激表达； 2）确定IAP抑制剂和刺痛的治疗作用 LKB1-MUT肿瘤中的激动剂； 3）评估IAP抑制剂与A结合的治疗作用 LKB1-MUT肿瘤中的PD-1阻滞剂。我们将检查IAP丁字轴的影响 GDH1（项目1）和FAK过度激活（项目3），以提高对LKB1免疫的理解响应信号传导。达到提案的目标，我们旨在提供使用IAP的临床前证据抑制剂，例如Birinapant，单独或与STING激动剂或ICI结合治疗肺癌患者与LKB1改变。