Deciphering LKB1-associated immunotherapy resistance in lung adenocarcinoma (LUAD)

解读肺腺癌 (LUAD) 中 LKB1 相关免疫治疗耐药性

基本信息

批准号：
10411665
负责人：
HAIAN FU
金额：
$ 222.93万
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/10411665
关键词：
Address BRAF gene Bioinformatics Biology Biometry Biostatistics Core Cancer Etiology Cancer Patient Cessation of life Cisplatin Clinic Clinical Clinical Trials Colon Carcinoma Combination immunotherapy Coupled Data Data Analyses Development Disease Epidermal Growth Factor Receptor Event Experimental Designs Fostering Frequencies Genes Glutamate Dehydrogenase Goals Grant Growth Hematologic Neoplasms Immune Immune checkpoint inhibitor Immune response Immunity Immunology Immunosuppression Immunotherapy Incidence Lead Leadership Light Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Medical Metabolic Methods Modeling Molecular Molecular Immunology Monitor Mutate Mutation Natural Immunity Nature New Agents Non-Small-Cell Lung Carcinoma Oncogenic Outcome PTK2 gene Patients Peer Review Persons Phase II Clinical Trials Primary Neoplasm Program Research Project Grants Protein Kinase Publications Publishing Refractory Regimen Regulatory T-Lymphocyte Research Research Project Grants Resistance Resources Role STK11 gene Signal Transduction Solid Neoplasm Source Supporting Cell Testing Therapeutic Translating Tumor Immunity Tumor Suppressor Proteins Tumor-infiltrating immune cells United States Universities aggressive therapy anti-cancer base cancer cell cancer immunotherapy central database checkpoint therapy clinical application clinical translation data sharing driver mutation effective therapy improved in vivo inhibitor innovation insight malignant breast neoplasm molecular pathology multidisciplinary mutant novel novel strategies novel therapeutic intervention novel therapeutics patient population personalized medicine personalized therapeutic programs resistance mechanism response targeted treatment therapeutic development therapeutically effective treatment strategy tumor tumor growth tumor progression tumorigenesis

项目摘要

SUMMARY Lung cancer is the leading cancer killer in the United States. Our team proposes to develop novel personalized therapeutic strategies by exploiting vulnerabilities and opportunities created by alterations in tumor suppressors in lung cancer. Specifically, we focus on the tumor suppressor LKB1, which is one of the most commonly mutated genes in lung adenocarcinoma (LUAD); LKB1 mutations are detected in 15-25% of LUAD, representing a major subpopulation of lung cancer patients. Despite the frequency, upward trajectory of incidence, and aggressive nature of disease, patients with LKB1-mutant LUAD not only have no targeted therapeutics available, but also show poor response to immune checkpoint inhibitors, demanding urgent development of effective therapeutic options. To address this critical gap, our revised application will capitalize on our integrated understanding of LKB1-loss–evoked tumor growth regulatory mechanisms and suppression of anticancer immunity to develop innovative clinical approaches for the treatment of patients with LKB1-mutant LUAD. New preliminary data from our team showed that 1) LKB1 loss allows metabolic dysregulation, such as glutamate dehydrogenase (GDH) activation by FAK, leading to increased regulatory T cells and immune suppression; 2) LKB1-loss-triggered inhibition of STING, a key innate immunity regulator, can be reversed by an IAP inhibitor, leading to reactivated immune response and its potent in vivo immune-dependent anticancer effect; and 3) FAK is activated in LKB1- deficient cancer cells and supports cell invasion and inhibits immune infiltration. These results lead to our central hypothesis that mutated LKB1 may exert its immune suppression function through a dysregulated anti-cancer immunity cycle mediated by key metabolic, innate immunity, and stromal regulatory factors. Targeting these factors may lead to novel approaches to re-activate anticancer immunity for effective therapeutic development in LUAD. We will address this hypothesis through three highly integrated Projects. Project 1 will examine the role of the FAK-GDH1 axis in immunotherapy resistance and tumor progression of LKB1-mutant LUAD. Project 2 will exploit our recently discovered LKB1-regulated IAP-JAK-STING signaling in LUAD to reverse immune suppression with an IAP inhibitor to enhance immunotherapy effect. Project 3 will focus on targeting FAK- mediated primary tumor progression in LKB1-mutant LUAD by performing a clinical trial with the combination of a FAK inhibitor and an immune checkpoint inhibitor coupled with mechanistic studies. The projects are supported by three cores, whose functions are administrative (Core 1), molecular pathology and immunology (Core 2), and bioinformatics and biostatistics (Core 3). This highly integrated effort builds on new discoveries from our established lung cancer team with more than 100 co-publications and with strong institutional support. We expect to advance lung cancer treatment strategies by new agent discovery (GDH1 inhibitors), new application of clinical stage IAP inhibitors, and a new phase II clinical trial of a FAK-targeted combination approach to overcome immunotherapy resistance of LKB1-mutant LUAD and bring treatment options to this patient population.

概括肺癌是美国领先的癌症杀手。我们的团队提议开发新颖的个性化通过利用肿瘤补充剂改变造成的脆弱性和机会来实现治疗策略在肺癌中。具体而言，我们专注于抑制肿瘤LKB1，这是最常见的突变之一肺腺癌（LUAD）中的基因；在15-25％的LUAD中检测到LKB1突变，代表一个主要肺癌患者的亚群。尽管发生了频率，事件的向上轨迹和侵略性疾病的性质，LKB1突变luAD的患者不仅没有可用的靶向疗法，而且还没有对免疫检查点抑制剂的反应不佳，要求紧急开发有效治疗选项。为了解决这个关键的差距，我们修订的应用程序将利用我们对 LKB1损坏 - 诱发的肿瘤生长调节机制和抗癌免疫的抑制用于治疗LKB1突变LUAD患者的创新临床方法。来自的新初步数据我们的团队表明1）LKB1损失允许代谢失调，例如谷氨酸脱氢酶（GDH） FAK激活，导致调节性T细胞增加和免疫抑制； 2）lkb1-loss触发抑制sting是一种关键的先天免疫调节剂，可以由IAP抑制剂逆转，导致重新激活免疫反应及其在体内免疫依赖性抗癌作用中的潜力； 3）fak在lkb1-中被激活缺陷癌细胞并支持细胞浸润并抑制免疫浸润。这些结果导致我们的中心假设突变的LKB1可能通过失调的抗癌药发挥其免疫抑制功能由关键代谢，先天免疫和基质调节因素介导的免疫细胞。针对这些因素可能导致新的方法重新激活抗癌免疫以进行有效的治疗发育在卢德。我们将通过三个高度集成的项目解决这一假设。项目1将检查角色 LKB1突变luAD的免疫疗法耐药性和肿瘤进展中的FAK-GDH1轴的。项目2 将利用我们最近发现的LKB1调节的IAP-JAK-sting信号传导以逆转免疫用IAP抑制剂抑制以增强免疫疗法的作用。项目3将专注于针对FAK- 通过进行临床试验，结合 FAK抑制剂和免疫抑制剂与机械研究结合。支持项目由三个核心（核心1），分子病理学和免疫学（核心2）和生物信息学和生物统计学（核心3）。这种高度综合的努力是建立在我们的新发现的基础上的建立了超过100个共同宣传和强大的机构支持的肺癌团队。我们期望为了推进新代理发现（GDH1抑制剂）的肺癌治疗策略，临床的新应用 IAP阶段抑制剂，以及针对FAK的组合方法的新的II期临床试验 LKB1突变剂LUAD的免疫疗法耐药性，并为该患者人群带来治疗选择。