Targeting the cytokine circuitry of KRAS-driven lung cancer

靶向 KRAS 驱动肺癌的细胞因子回路

基本信息

批准号：
10172854
负责人：
David A Barbie
金额：
$ 41.57万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10172854
关键词：
Animal Model Antimitotic Agents Antiviral Agents Antiviral Response Autologous Automobile Driving Biological Models CXCL10 gene Cancer Model Cell Line Cell Survival Cell-Mediated Cytolysis Cells Colorectal Cancer Combined Modality Therapy DNA DNA Damage Data Detection Development EZH2 gene Enzymes Epigenetic Process Evaluation Feedback Genetic Genetic Transcription Genetically Engineered Mouse Goals Human IRF3 gene Immune Immune checkpoint inhibitor Immune signaling Immunocompetent Inflammatory Interleukin-1 Interleukin-6 KRAS oncogenesis KRAS2 gene Laboratories Lung Neoplasms MEK inhibition MEKs Malignant neoplasm of lung Measures Mediating Mitochondria Mitochondrial DNA Mitotic Modeling Mus Mutate Mutation Neutrophil Infiltration Non-Small-Cell Lung Carcinoma Oncogenes Output PD-1 blockade PD-1 inhibitors Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phosphotransferases Play Population Production Proteins Public Health RANTES RPS27 gene Refractory Repression Research Research Project Grants Resistance Role STAT1 gene STAT3 gene STING agonists STK11 gene Signal Pathway Signal Transduction Specimen Stimulator of Interferon Genes T cell response T-Lymphocyte TBK1 gene TP53 gene Therapeutic Tumor Immunity Tumorigenicity Up-Regulation Validation Viral anti-PD-1 autocrine checkpoint therapy chemokine clinical efficacy cytokine cytotoxic cytotoxicity effector T cell epigenetic silencing immunogenicity in vivo inhibitor/antagonist mutant neoplastic cell novel patient derived xenograft model patient subsets pre-clinical preclinical development predictive marker recruit response sensor synergism targeted treatment tumor tumor microenvironment tumorigenesis tumorigenic

项目摘要

The goal of this research project proposal is to co-opt dysfunctional innate immune signaling in KRAS- driven lung cancers as a therapeutic vulnerability. Specifically, my laboratory has focused for many years on targeting TBK1 to inhibit the production of cytokines and chemokines such as IL-6 and CCL5 that are pro- tumorigenic and immune suppressive. For example, TBK1 inhibition sensitizes tumors to MEK inhibition, as well as PD-1 blockade. Over the past several years it has also become increasingly apparent that viral sensing pathways, such as RIG-I/MAVS or cGAS/STING play a key role in re-directing TBK1 to activate IRF3/STAT1 and initiate a cytotoxic anti-viral response. How KRAS mutant lung cancers, especially those with STK11/LKB1 co-mutation, avoid this response and preferentially activate NF-κB/STAT3 survival signaling has remained unclear. While developing triple combination therapies to inhibit TBK1/MEK signaling and suppress adaptive transcriptional feedback, we made the serendipitous observation that KRAS-LKB1 (KL) mutant lung cancers epigenetically silence STING. Detailed studies in KL cells unveiled a mechanistic connection between enhanced DNMT1 activity and the need to avoid detection of mitochondrial DNA, which accumulates due to damaged mitochondria. Re-activating STING expression in KL cells results in cellular cytotoxicity and enhanced immunogenicity, especially when combined with STING agonism. Thus, instead of inhibiting multiple signaling pathways downstream KRAS, these studies uncover a straightforward vulnerability that could be more readily co-opted therapeutically. The broad, long term objective of this proposal is therefore to characterize the epigenetic mechanism of STING silencing and to co-opt this state into a tumor vulnerability. Forcing cells to deal with the consequences of STING re-expression, while driving its activity via DNA damage or direct STING agonism, has important therapeutic potential for this major subset of KRAS-driven lung cancer. Given the unclear therapeutic window of targeting three or more KRAS downstream pathways, which is required for long-term durable response in animal models, this simpler strategy, which can also re-engage anti-tumor immunity, has significant potential. Moreover, in addition to the in vivo studies we propose, our novel model system using patient-derived xenograft and direct patient-derived organotypic tumor spheroids (XDOTS and PDOTS) provides rapid validation in actual explanted tumors. Specific aims are to: 1) Optimize strategies to reverse epigenetic silencing of STING in KL tumors, 2) Develop combination therapy strategies with specific agents that promote mitotic slippage, and 3) Utilize immune-competent models to explore the direct role of STING priming on adaptive T cell responses. Through these complementary studies, the goal is to rewire the cytokine circuitry of KRAS-driven lung cancer to engage this cytotoxic anti-viral signaling machinery and ultimately to overcome intrinsic resistance to immune checkpoint inhibitor therapy.

该研究项目提案的目标是在 KRAS 中选择功能失调的先天免疫信号- 具体来说，我的实验室多年来一直致力于肺癌的治疗。靶向 TBK1 抑制细胞因子和趋化因子（例如 IL-6 和 CCL5）的产生例如，TBK1 抑制也会使肿瘤对 MEK 抑制敏感。随着 PD-1 阻断，在过去几年中，病毒传感也变得越来越明显。 RIG-I/MAVS 或 cGAS/STING 等通路在重新引导 TBK1 激活 IRF3/STAT1 中发挥关键作用 KRAS 突变肺癌，尤其是带有 STK11/LKB1 的肺癌，如何启动细胞毒性抗病毒反应。共突变，避免这种反应并优先激活 NF-κB/STAT3 生存信号仍然存在不清楚。在开发三联疗法来抑制 TBK1/MEK 信号传导并抑制适应性转录反馈，我们偶然发现 KRAS-LKB1 (KL) 突变肺癌对 KL 细胞的表观遗传学沉默 STING 的详细研究揭示了增强之间的机制联系。 DNMT1 活性以及避免检测线粒体 DNA 的需要，线粒体 DNA 因受损而积累重新激活 KL 细胞中的 STING 表达会导致细胞毒性并增强。免疫原性，特别是与 STING 激动剂结合时，而不是抑制多种信号传导。 KRAS 下游通路，这些研究揭示了一个简单的漏洞，可以更容易地治疗上的增选。因此，该提案的广泛、长期目标是表征表观遗传机制 STING 沉默并将这种状态纳入肿瘤脆弱性，迫使细胞应对后果。 STING 重新表达，同时通过 DNA 损伤或直接 STING 激动来驱动其活性，具有重要意义鉴于 KRAS 驱动的肺癌这一主要亚型的治疗潜力尚不清楚。针对三个或更多 KRAS 下游途径，这是动物长期持久反应所必需的模型中，这种更简单的策略还可以重新激活抗肿瘤免疫，具有巨大的潜力。除了我们提出的体内研究之外，我们的新颖模型系统使用患者来源的异种移植物和直接患者来源的器官型肿瘤球体（XDOTS 和 PDOTS）在实际移植中提供快速验证具体目标是：1) 优化逆转 KL 肿瘤中 STING 表观遗传沉默的策略，2) 制定与促进有丝分裂滑移的特定药物的联合治疗策略，以及 3) 利用免疫活性模型探索 STING 启动对适应性 T 细胞反应的直接作用。这些补充研究的目标是重新连接 KRAS 驱动的肺癌的细胞因子回路，以参与这种细胞毒性抗病毒信号机制并最终克服对免疫检查点的内在抵抗抑制剂治疗。