Characterizing the XRN1 exoribonuclease as a therapeutic target in non-small cell lung cancer

项目摘要/摘要 非小细胞肺癌(NSCLC)是全球癌症相关死亡的主要原因。最新进展 抑制突变致癌蛋白的靶向分子疗法和抑制PD的免疫疗法- 1/PD-L1通路改善了部分非小细胞肺癌患者的预后。然而，靶向治疗 仅对存在可操作的基因改变的非小细胞肺癌有效。此外，抗PD-1/PD-L1 免疫检查点抑制剂对表达高水平PD-L1或具有 高肿瘤突变负担。因此，缺乏这些特征的非小细胞肺癌患者不能从靶向治疗中受益 而且不太可能从免疫疗法中获益，强调需要确定新的治疗方法 这种疾病的靶点。这个项目试图确定XRN1外切核糖核酸酶的特性，它在细胞内起作用 RNA降解，作为非小细胞肺癌可能具有广泛治疗潜力的靶点。我的初步数据显示 XRN1的失活诱导了人类非小细胞肺癌细胞系的一部分细胞死亡。在一只可植入的小鼠中 在肿瘤模型中，XRN1缺失可与抗PD-1免疫治疗协同增强肿瘤的清除。目标1 将确定在人类XRN1基因缺失后介导细胞致死性的分子信号通路 NSCLC细胞株。目的2将评估XRN1缺失对抗PD-1小鼠非小细胞肺癌模型的影响 免疫疗法。目的3将确定XRN1基因在人类NSCLC肿瘤中的表达是否可能作为一种 预测抗PD-1免疫治疗反应的生物标志物。建议的长期目标 研究将获得关于RNA新陈代谢如何调节癌细胞存活和抗肿瘤的基本见解 肿瘤免疫和建立RNA代谢通路作为非小细胞肺癌潜在的治疗靶点。 申请人邹涛博士是达纳-法伯癌症研究所(DFCI)的肿瘤学家。他80%的时间 从事研究和职业发展活动，20%的时间在临床实践中照顾病人 患有肺癌。邹博士概述了一项五年职业发展计划，这将使他能够实现自己的 目标是领导一个独立的实验室，在 RNA生物学与肺癌免疫治疗。邹博士将在导师的指导下进行拟议的研究 马修·迈耶森博士是一位肺癌生物学专家，有良好的独立培训记录 学术癌症研究中的研究人员。与邹博士科学咨询专家成员一起 Meyerson博士将确保邹丽红博士获得先天免疫RNA感应方面的额外培训， 肿瘤免疫学、使用人类生物标本的翻译研究和计算生物学。邹某博士将 主要在DFCI进行拟议的研究，并将利用他在 布罗德研究所和哈佛医学院。DFCI是一个内容丰富的研究社区，有着卓越的记录 培养成功的内科科学家。DFCI为邹丽红博士的研究提供了理想的环境 在过渡到独立的学术职位之前，应具备专业知识并从事职业发展活动。

PROJECT SUMMARY/ABSTRACT Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. The development of targeted molecular therapies that inhibit mutant oncogenic proteins and immunotherapies that inhibit the PD- 1/PD-L1 pathway have improved outcomes for subsets of patients with NSCLC. However, targeted therapies are only effective against NSCLCs that harbor actionable genetic alterations. In addition, anti-PD-1/PD-L1 immune checkpoint inhibitors are most effective against NSCLCs that express high levels of PD-L1 or have a high tumor mutation burden. Thus, patients with NSCLCs that lack these features do not benefit from targeted therapies and are less likely to benefit from immunotherapies, emphasizing the need to identify novel therapeutic targets in this disease. This project seeks to characterize the XRN1 exoribonuclease, which functions in cellular RNA degradation, as a target that may have broad therapeutic potential in NSCLC. My preliminary data show that XRN1 inactivation induces cell lethality in a subset of human NSCLC cell lines. In an implantable mouse tumor model, XRN1 deletion can synergize with anti-PD-1 immunotherapy to enhance tumor eradication. Aim 1 will define the molecular signaling pathways that mediate cell lethality after XRN1 deletion in a subset of human NSCLC cell lines. Aim 2 will assess the impact of XRN1 deletion in mouse NSCLC models of anti-PD-1 immunotherapy. Aim 3 will determine whether XRN1 gene expression in human NSCLC tumors may serve as a predictive biomarker for treatment response to anti-PD-1 immunotherapy. The long-term goals of the proposed research are to gain fundamental insights into how RNA metabolism regulates cancer cell survival and anti- tumor immunity and to establish RNA metabolism pathways as potential therapeutic targets in NSCLC. The applicant, Dr. Tao Zou, is an oncologist at Dana-Farber Cancer Institute (DFCI). He spends 80% of his time engaged in research and career development activities and 20% of his time in clinical practice caring for patients with lung cancer. Dr. Zou has outlined a five-year career development plan that will enable him to achieve his goal of leading an independent laboratory that conducts basic and translational research at the intersection of RNA biology and lung cancer immunotherapy. Dr. Zou will perform the proposed research under the mentorship of Dr. Matthew Meyerson, an expert in lung cancer biology with a strong record of training independent investigators in academic cancer research. Together with expert members of Dr. Zou’s Scientific Advisory Committee, Dr. Meyerson will ensure that Dr. Zou will obtain additional training in innate immune RNA sensing, tumor immunology, translational studies using human biospecimens, and computational biology. Dr. Zou will conduct the proposed research primarily at DFCI and will leverage additional resources available to him at the Broad Institute and Harvard Medical School. DFCI is a rich research community with a distinguished track record of training successful physician-scientists. DFCI provides the ideal environment for Dr. Zou to build his research expertise and engage in career development activities prior to transitioning to an independent academic position.