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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.

总结