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

将 XRN1 核糖核酸外切酶表征为非小细胞肺癌的治疗靶点

基本信息

批准号：
10656174
负责人：
Tao Zou
金额：
$ 20.88万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656174
关键词：
Advisory Committees Basic Science Biology Biopsy CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer Model Cancer cell line Cell Death Cell Survival Cells Clinical Communities Computational Biology Cyclic AMP-Dependent Protein Kinases Cytoplasm DNA Sequence Alteration Dana-Farber Cancer Institute Data Development Development Plans Disease Double-Stranded RNA Ensure Environment Enzymes Eukaryotic Initiation Factors Exoribonucleases Flow Cytometry Funding Gene Expression Gene Expression Profiling Genes Genetic Goals Human Immune Immune checkpoint inhibitor Immunotherapy Implant Interferon Type I Laboratories Laboratory Research Link Malignant neoplasm of lung Mediating Mentorship Modeling Molecular Mus Mutation Non-Small-Cell Lung Carcinoma Oncogenic Oncologist PD-1 inhibitors PD-1/PD-L1 PDL1 pathway Pathway interactions Patient Care Patient-Focused Outcomes Patients Phosphorylation Physicians Positioning Attribute Proteins RNA RNA Degradation RNA metabolism Regimen Research Research Personnel Research Proposals Resistance Resources Scientist Signal Induction Signal Pathway Signal Transduction Therapeutic Time Training Translational Research Tumor Immunity United States anti-PD-1 anti-PD-1/PD-L1 anti-tumor immune response anticancer research biological adaptation to stress cancer cell cancer immunotherapy career development checkpoint inhibition clinical practice cohort cytokine experimental study gene induction genome-wide immune RNA immune cell infiltrate improved improved outcome in vivo innovation insight loss of function lung cancer cell medical schools member molecular targeted therapies mortality mutant new therapeutic target patient subsets pharmacologic poly A specific exoribonuclease predictive marker programmed cell death ligand 1 programs protein kinase R recruit research and development response biomarker sensor synergism targeted treatment therapeutic target translational study treatment response treatment strategy tumor tumor eradication tumor immunology tumor microenvironment

项目摘要

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.

项目摘要/摘要非小细胞肺癌（NSCLC）是全球癌症死亡率的主要原因靶向分子疗法的抑制突变体致癌蛋白和免疫性的侵害的分子疗法 1/pd-L1途径已改善了具有NSCLC的PATIETS的结果仅针对NSCLC tharbor可行的遗传高度免疫检查点抑制剂对表达高水平PD-L1或具有的NSCLC最有效高肿瘤突变负担。疗法并喜欢从免疫疗法中受益，强调识别新型治疗的需求该疾病的靶标。 RNA降解，作为在NSCLC中具有广泛治疗潜力的靶标。 XRN1失活在人NSCLC细胞的一部分中诱导细胞致死性。肿瘤模型，XRN1删除可以与抗PD-1免疫疗法协同作用，以增强肿瘤消除。将定义XRN1缺失后介导细胞致死性的分子信号传导途径 NSCLC细胞系2。免疫治疗3将决定人NSCLC肿瘤中的XRN1基因表达是否可以作为对抗PD-1免疫疗法的治疗反应的预测性生物标志物。研究是为了获得有关RNA代谢如何调节癌细胞存活和抗 - 的基本见解肿瘤免疫并建立RNA代谢途径作为NSCLC的潜在治疗靶标。申请人Tao Zou博士是Dana-Farber癌症研究所（DFCI）的肿瘤学家。从事研究和职业发展活动，并为患者进行20％的临床实践训练时间 Zou博士概述了一项五年的职业发展计划领导和依赖实验室的目标，该实验室在交集的交集中进行基本和翻译 RNA生物学和肺癌不受欢迎。肺癌生物学专家Matthew Meyerson博士拥有良好的培训独立记录学术癌症研究的研究人员与Zou博士的科学咨询委员会，梅耶森博士将确保博士肿瘤免疫学，使用人类生物测量的翻译研究和计算生物学。主要在DFCI进行拟议的研究，并将利用他在 Broad Institute and Harvard Medical School。培训成功的医师科学家。在过渡到独立的学术职位之前，专业知识和英语在职业发展活动中。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells.

XRN1 缺失会在干扰素激活的癌细胞中诱导 PKR 依赖性细胞致死。

DOI：
10.1101/2023.08.01.551488
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Zou,Tao;Zhou,Meng;Gupta,Akansha;Zhuang,Patrick;Fishbein,AlyssaR;Wei,HopeY;Zhang,Zhouwei;Cherniack,AndrewD;Meyerson,Matthew
通讯作者：
Meyerson,Matthew