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

项目总结/摘要 非小细胞肺癌（NSCLC）是全球癌症相关死亡率的主要原因。发展 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NSCLC患者亚群的结局。然而，靶向治疗 仅对具有可操作的遗传改变的NSCLC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或具有高水平PD-L1的NSCLC最有效。 高肿瘤突变负荷。因此，缺乏这些特征的NSCLC患者不能从靶向治疗中获益。 免疫治疗的可能性较小，强调需要确定新的治疗方法。 针对这种疾病。该项目旨在表征XRN 1核糖核酸外切酶，其在细胞中起作用。 RNA降解，作为可能在NSCLC中具有广泛治疗潜力的靶点。我的初步数据显示 XRN 1失活诱导人NSCLC细胞系亚群中的细胞致死性。在一个可植入的老鼠体内 在肿瘤模型中，XRN 1缺失可以与抗PD-1免疫疗法协同作用以增强肿瘤根除。要求1 将定义在人的一个亚群中XRN 1缺失后介导细胞致死的分子信号传导途径。 NSCLC细胞系。目的2将评估XRN 1缺失在抗PD-1小鼠NSCLC模型中的影响， 免疫疗法目的3将确定XRN 1基因在人类非小细胞肺癌肿瘤中的表达是否可以作为一种治疗方法。 用于对抗PD-1免疫疗法的治疗应答的预测性生物标志物。拟议的长期目标 研究是为了获得关于RNA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代谢途径作为NSCLC的潜在治疗靶点。 申请人邹涛博士是Dana-Farber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 患上了肺癌邹博士概述了一个五年职业发展计划，这将使他能够实现他的目标。 领导一个独立实验室的目标，在以下交叉点进行基础和转化研究： 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 Matthew Meyerson博士是肺癌生物学专家，在独立培训方面有着良好的记录。 学术癌症研究的研究人员。与邹博士科学顾问的专家成员一起 Meyerson博士将确保邹博士获得先天免疫RNA传感方面的额外培训， 肿瘤免疫学、使用人类生物样本的转化研究和计算生物学。邹医生会 进行拟议的研究主要在DFCI，并将利用额外的资源，他在 布罗德研究所和哈佛医学院。DFCI是一个丰富的研究社区，具有杰出的业绩记录 培养成功的医学科学家DFCI为邹博士提供了理想的研究环境 专业知识，并在过渡到独立的学术职位之前从事职业发展活动。

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.