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

• 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
• 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

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.

项目摘要 肺癌是美国癌症相关死亡的主要原因。非小细胞肺癌 (非小细胞肺癌)是最常见的肺癌类型，尽管积极的治疗策略包括 肺癌患者的内科治疗、手术切除和放射治疗的5年生存率 仍然令人沮丧。最近，美国食品和药物管理局(FDA)批准了几个免疫检查站 以抑制剂为基础的治疗非小细胞肺癌，确立免疫疗法为有效的治疗方法 非小细胞肺癌的选择和标准护理治疗。尽管如此，许多患者对免疫没有反应。 检查点封锁(ICB)和KRAS和STK11减刑患者亚组(KL) 出现了一种对ICB耐药的特别具有侵袭性、免疫抑制的非小细胞肺癌。我们的团队已经 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，一种 抗肺癌免疫反应中的关键蛋白，干扰素基因的刺激物(STING)被恢复。 当随后通过对纺锤体的脉冲抑制来提供刺痛通路的刺激时 组装检查点蛋白，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突变的非小细胞肺癌的临床样本中得到验证， 这些样本现在可以用于研究。对这一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，但它不会产生新的抗原 推动持久的抗肿瘤免疫反应。幸运的是，Mps1与CDC2样蛋白有相同的激酶同源性 作为信使核糖核酸剪接的关键调节因子，激酶(CLK2)和双Mps1/CLK2抑制剂已经被开发出来。这 提供独特的机会，通过额外的潜水持久的抗肿瘤免疫反应 基因剪接的同步药理干扰。事实上，剪接的药物调节 最近被证明是一种决定性的、未被开发的方法来产生新的抗原，从而产生抗肿瘤 免疫反应。因此，这一奖学金提案的总体目标是提供高级博士后 对转化型癌症免疫治疗研究进行培训，同时评估一种新的增强 高度侵袭性和抗药性的非小细胞肺癌的免疫原性。我们将通过(1)验证来实现这一点 ICB耐药的临床标本中表遗传下调STING和脉冲MPS1抑制的作用 KL突变的非小细胞肺癌和(2)检测双重Mps1/CLK2的mRNA剪接断裂和新抗原的产生 抑制剂处理KL突变的非小细胞肺癌。这些目标将共同寻求改善治疗结果 同时加强训练有素的内科科学家队伍。