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：
10424442
负责人：
David A Barbie
金额：
$ 40.74万
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/10424442
关键词：
Animal Model Antimitotic 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 inhibitor therapy 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的是在KRAS-中采用功能失调的先天免疫信号传导驱动的肺癌是一种治疗脆弱性。具体来说，我的实验室已经专注于多年靶向TBK1抑制细胞因子和趋化因子（例如IL-6和CCL5）的产生肿瘤和免疫抑制。例如，TBK1也会抑制肿瘤对MEK抑制作用，作为PD-1封锁。在过去的几年中，病毒感官也变得越来越明显途径，例如RIG-I/MAV或CGAS/sting在重新指导TBK1以激活IRF3/STAT1方面起关键作用并引发细胞毒性抗病毒反应。 KRAS突变肺癌，尤其是患有STK11/LKB1的癌症共同享受，避免这种响应并优先激活NF-κB/STAT3存活信号已保持不清楚。在开发三重组合疗法以抑制TBK1/MEK信号并抑制适应性的同时转录反馈，我们进行了偶然的观察，即Kras-LKB1（KL）突变肺癌表观遗传上的沉默刺痛。 KL细胞中的详细研究揭示了增强的机械联系 DNMT1活性以及避免检测到线粒体DNA的需求，由于损坏而累积线粒体。重新激活KL细胞中的刺激表达会导致细胞细胞毒性并增强免疫原性，尤其是与刺激性激动剂结合使用时。那，而不是抑制多个信号传导途径下游KRAS，这些研究发现了一个简单的脆弱性，可以更容易地进行治疗。因此，该提案的广泛，长期目标是表征刺痛沉默，并将这种状态陷入肿瘤脆弱性。强迫细胞处理后果通过DNA损伤或直接的刺痛激动剂在驱动其活动时，刺痛的重新表达很重要这是KRAS驱动的肺癌的主要子集的治疗潜力。鉴于不清楚的治疗窗口针对三个或多个KRAS下游途径，这是动物长期持久反应所必需的模型，这种简单的策略也可以重新接触抗肿瘤免疫，具有巨大的潜力。而且，除了我们提出的体内研究外，我们的新型模型系统使用患者衍生的Xenographogroticon和Direct 患者衍生的有机肿瘤球体（XDOTS和PDOTS）在实际外植物中提供了快速验证肿瘤。具体目的是：1）优化逆转KL肿瘤刺激表观遗传沉默的策略，2）与促进有丝分裂片的特定药物制定组合疗法策略，3）免疫能力模型探索刺激启动在适应性T细胞反应上的直接作用。通过这些完整的研究，目的是将KRAS驱动的肺癌的细胞因子电路重新连接以参与这种细胞毒性抗病毒信号机制，最终以克服对免疫检查点的内在抗性抑制剂疗法。