Dual targeting of cGAS-STING and splicing to prime lung cancer immunogenicity

cGAS-STING 和剪接的双重靶向以提高肺癌免疫原性

基本信息

批准号：
10749760
负责人：
Patrick C Gedeon
金额：
$ 7.61万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-17 至 2025-07-16
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749760
关键词：
3-Dimensional Accounting Antigen Presentation Antineoplastic Agents Antitumor Response Biology CDC2 gene CXCL10 gene Cancer Etiology Cells Cessation of life Clinical Commuting Cytoprotection Defect Diagnosis Dinucleoside Phosphates Disease Epigenetic Process Excision Extravasation Fellowship Foundations Gene Expression Generations Goals Immune Immune checkpoint inhibitor Immune response Immunologics Immunosuppression Immunotherapy Induced Mutation Interferon Type I KRAS2 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Medical Messenger RNA Methods Microfluidics Mitochondrial DNA Modeling Modernization Mutate Mutation Natural Immunity Non-Small-Cell Lung Carcinoma Oncogenic Operative Surgical Procedures PDL1 inhibitors Pathway interactions Patient-Focused Outcomes Patients Peptides Periodicity Phosphotransferases Physicians Physiologic pulse Protein Isoforms Proteins Public Health Quality of life RNA Splicing Radiation therapy Refractory Research Resistance Role STAT1 gene STK11 gene Sampling Scientist Secondary to Source Spliceosomes Stimulator of Interferon Genes Stimulus Subgroup Survival Rate System T-Lymphocyte Technology Therapeutic Thoracic Surgical Procedures Training Tumor Immunity United States United States Food and Drug Administration Validation aggressive therapy anti-tumor immune response cancer cell cancer immunotherapy cytokine cytotoxicity derepression ds-DNA epigenetic silencing experience immune checkpoint blockade immunogenic immunogenicity improved inhibitor micronucleus mutant neoantigens novel strategies novel therapeutic intervention novel therapeutics patient subsets pharmacologic post-doctoral training promoter recruit refractory cancer standard of care success therapeutically effective therapy outcome treatment strategy tumor

项目摘要

Project Summary Lung cancer is the leading cause of cancer-related death in the United States. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and despite aggressive treatment strategies that include medical therapy, surgical resection, and radiation therapy, 5-year survival rates for patients with lung cancer remain dismal. Recently, the US Food and Drug Administration (FDA) approved several immune checkpoint inhibitor-based therapies for the treatment of NSCLC, establishing immunotherapy as an effective therapeutic option and standard-of-care treatment for NSCLC. Despite this, many patients fail to respond to immune checkpoint blockade (ICB) and the subgroup of patients with KRAS and STK11 commutations (KL) has emerged as a particularly aggressive, immunosuppressive form of NSCLC resistant to ICB. Our group has recently discovered that by treating KL-mutated NSCLC with epigenetic de-repressing agents, expression of a key protein in the immune response against lung cancer, stimulator of interferon genes (STING), is restored. When stimulus for the STING pathway is subsequently provided through pulsed inhibition of a spindle assembly checkpoint protein, monopolar spindle 1 (MPS1), potent anti-tumor responses occur, restoring sensitivity to ICB. While these findings have yet to be validated in clinical samples of KL-mutated NSCLC, these samples are now available to use for study. Validation of this therapeutic strategy will show that it is possible to overcome KL-mutation induced immunosuppression, though, it does not generate neoantigens to drive durable anti-neoplastic immune responses. Fortunately, MPS1 shares kinase homology with CDC2-like kinase (CLK2), a key regulator of mRNA splicing, and dual MPS1/CLK2 inhibitors have been developed. This provides the unique opportunity to additionally dive durable anti-tumor immune responses through simultaneous pharmacological disruption of mRNA splicing. Indeed, pharmacological modulation of splicing was recently demonstrated as a definitive, untapped method to generate neoantigens that elicit anti-tumor immune responses. The overall goal of this fellowship proposal is, therefore, to provide advanced post-doctoral training in translational cancer immunotherapy research while evaluating a novel approach to enhance immunogenicity in a highly aggressive and resistant form of NSCLC. We will accomplish this by (1) validating the effect of epigenetic de-repression of STING and pulsed MPS1 inhibition in clinical samples of ICB-resistant, KL-mutated NSCLC and (2) examining mRNA splice disruption and neoantigen generation in dual MPS1/CLK2 inhibitor treated KL-mutated NSCLC. Together these aims will seek to improve therapeutic outcomes for patients with NSCLC while enhancing the pool of highly trained physician-scientists.

项目概要肺癌是美国癌症相关死亡的主要原因。非小细胞肺癌（NSCLC）是最常见的肺癌类型，尽管采取了积极的治疗策略，包括药物治疗、手术切除和放射治疗，肺癌患者的 5 年生存率保持沮丧。近日，美国食品药品监督管理局（FDA）批准了多个免疫检查点基于抑制剂的治疗非小细胞肺癌，确立免疫疗法作为一种有效的治疗方法 NSCLC 的选择和标准护理治疗。尽管如此，许多患者仍无法对免疫做出反应检查点封锁 (ICB) 和 KRAS 和 STK11 突变 (KL) 患者亚组 NSCLC 是一种特别具有侵袭性、免疫抑制性的类型，对 ICB 具有耐药性。我们组有最近发现，通过用表观遗传去抑制剂治疗 KL 突变的非小细胞肺癌，肺癌免疫反应中的关键蛋白——干扰素基因刺激物（STING）得到恢复。当随后通过纺锤体的脉冲抑制提供对 STING 通路的刺激时装配检查点蛋白，单极纺锤体 1 (MPS1)，发生有效的抗肿瘤反应，恢复对 ICB 的敏感性。虽然这些发现尚未在 KL 突变 NSCLC 的临床样本中得到验证，这些样本现在可用于研究。这种治疗策略的验证将表明它是有可能克服 KL 突变引起的免疫抑制，但它不会产生新抗原驱动持久的抗肿瘤免疫反应。幸运的是，MPS1 与 CDC2 类似物具有激酶同源性激酶 (CLK2)（mRNA 剪接的关键调节因子）和 MPS1/CLK2 双重抑制剂已被开发出来。这提供了独特的机会来进一步挖掘持久的抗肿瘤免疫反应同时药理学破坏 mRNA 剪接。事实上，剪接的药理调节最近被证明是一种确定的、尚未开发的方法来产生引发抗肿瘤的新抗原免疫反应。因此，该奖学金提案的总体目标是提供高级博士后转化癌症免疫治疗研究培训，同时评估一种新方法来增强高度侵袭性和耐药性 NSCLC 中的免疫原性。我们将通过 (1) 验证来实现这一点 STING 表观遗传去抑制和脉冲 MPS1 抑制对 ICB 耐药临床样本的影响， KL 突变 NSCLC 和 (2) 检查双 MPS1/CLK2 中的 mRNA 剪接破坏和新抗原生成抑制剂治疗 KL 突变 NSCLC。这些目标将共同寻求改善治疗结果 NSCLC 患者，同时增强训练有素的医师科学家队伍。