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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.

本研究项目提案的目标是利用KRAS中功能失调的先天性免疫信号。导致肺癌是治疗上的弱点。具体地说，我的实验室多年来一直专注于靶向TBK1抑制细胞因子和趋化因子的产生，如IL-6和CCL5，这些细胞因子和趋化因子是促进致癌和免疫抑制。例如，抑制TBK1也会使肿瘤对MEK抑制敏感作为PD-1封锁。在过去的几年里，病毒感应也变得越来越明显 RIG-I/MAV或cGAS/STING等通路在重定向TBK1激活IRF3/STAT1中起着关键作用并启动一种细胞毒性抗病毒反应。KRAS如何突变肺癌，特别是带有STK11/LKB1的肺癌共突变，避免这一反应并优先激活NF-κB/STAT3生存信号已保留不清楚。同时开发三联疗法来抑制TBK1/MEK信号转导和抑制适应性转录反馈，我们偶然观察到KRAS-LKB1(KL)突变的肺癌表观遗传的沉默刺痛。对KL细胞的详细研究揭示了增强的 DNMT1活性和需要避免检测到线粒体DNA，线粒体DNA因损伤而积聚线粒体。重新激活STING在KL细胞中的表达导致细胞毒性和增强免疫原性，尤指与刺激性结合时。因此，不是抑制多个信令在KRAS下游的路径上，这些研究发现了一个直接的漏洞，可能更容易在治疗上有所选择。因此，这项提议的广泛、长期的目标是表征表观遗传机制刺痛沉默，并将这种状态拉拢成肿瘤的脆弱性。迫使细胞应对后果在通过DNA损伤或直接的刺激性来驱动其活性的同时，刺激性再表达的研究具有重要的意义 KRAS驱动的肺癌的这一主要亚型的治疗潜力。鉴于目前尚不清楚的治疗窗口靶向三条或更多KRAS下游通路，这是动物长期持久反应所必需的模型，这一更简单的策略，也可以重新进行抗肿瘤免疫，具有巨大的潜力。此外，除了我们提出的体内研究外，我们的新模型系统使用患者来源的异种移植和直接患者衍生的器官型肿瘤球体(XDOTS和PDOTS)在实际解释中提供了快速验证肿瘤。具体目标是：1)优化逆转KL肿瘤中STIN的表观遗传沉默的策略，2) 开发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，以探索刺激性刺激在适应性T细胞反应中的直接作用。穿过这些互补性研究的目标是重新连接KRAS驱动的肺癌的细胞因子电路这种细胞毒性抗病毒信号传递机制最终克服了免疫检查点的内在抵抗力抑制物疗法。