Mechanisms of action and therapeutic targeting of the CARM1-NFIB axis in small cell lung cancer

CARM1-NFIB 轴在小细胞肺癌中的作用机制和治疗靶向

基本信息

批准号：
10657854
负责人：
MARK T. BEDFORD
金额：
$ 65.14万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657854
关键词：
ATAC-seq Address C-terminal Cancer Model Cancer Patient Cell Separation Collaborations Complex Crystallography Development Epigenetic Process Evolution Excision FDA approved Family Future Genetic Transcription Genetically Engineered Mouse Grant Knock-in Mouse Knowledge Life Expectancy Life Extension Longevity Maintenance Malignant - descriptor Malignant Neoplasms Maps Methylation Methyltransferase Modeling Molecular Mus Mutant Strains Mice Mutation NFIB gene Neoplasm Metastasis Oncogenic Pathogenesis Pathway interactions Property Rationalization Reader Reporting Research Role Signal Transduction Site Testing Therapeutic Transcription Coactivator Translations Tumor Promotion Validation arginine methyltransferase coactivator-associated arginine methyltransferase 1 conditional knockout epigenetic profiling experimental study human disease in vivo inhibitor lung cancer cell model development mouse model mutant neoplastic cell novel overexpression patient derived xenograft model pre-clinical preclinical study programs protein complex recombinase recruit response single-cell RNA sequencing small cell lung carcinoma small molecule inhibitor targeted treatment therapeutic target transcription factor transcriptome sequencing tumor heterogeneity tumor progression

ATAC-seq Address C-terminal Cancer Model Cancer Patient Cell Separation Collaborations Complex Crystallography Development Epigenetic Process Evolution Excision FDA approved Family Future Genetic Transcription Genetically Engineered Mouse Grant Knock-in Mouse Knowledge Life Expectancy Life Extension Longevity Maintenance Malignant - descriptor Malignant Neoplasms Maps Methylation Methyltransferase Modeling Molecular Mus Mutant Strains Mice Mutation NFIB gene Neoplasm Metastasis Oncogenic Pathogenesis Pathway interactions Property Rationalization Reader Reporting Research Role Signal Transduction Site Testing Therapeutic Transcription Coactivator Translations Tumor Promotion Validation arginine methyltransferase coactivator-associated arginine methyltransferase 1 conditional knockout epigenetic profiling experimental study human disease in vivo inhibitor lung cancer cell model development mouse model mutant neoplastic cell novel overexpression patient derived xenograft model pre-clinical preclinical study programs protein complex recombinase recruit response single-cell RNA sequencing small cell lung carcinoma small molecule inhibitor targeted treatment therapeutic target transcription factor transcriptome sequencing tumor heterogeneity tumor progression

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项目摘要

ABSTRACT Treatment options for small cell lung cancer (SCLC) patients have remained largely unchanged for 3 decades, with no new FDA-approved treatments for 20 years, and no targeted therapies. We recently performed a screen for targets of an arginine methyltransferase called CARM1 and identified the NFI family of transcription factors as substrates for this PRMT. Importantly, NFIB harbors both oncogenic and metastatic promoting activities in the context of SCLC development. We confirmed that CARM1 functions as a transcriptional coactivator for NFIB. Based on these finding, we hypothesize that CARM1 methylation of NFIB is critical for its tumor-promoting functions. To further support this premise, we have generated a Nfib knockin mouse that harbors a R-to-K mutation in the CARM1 methylation site. When this mouse is crossed onto a SCLC genetically engineered mouse model (GEMM) the life expectancy of these mice is lengthened by a third (from 200 to 300 days), which is almost identical to the impact of Carm1-loss in the same GEMM. These finding raise the possibility of targeting SCLC with CARM1 small molecule inhibitors. We have also identified an effector molecule (TRIM29) for the CARM1 methylation site on NFIB. In this proposal we plan to: (1) perform a deep mechanistic analysis of this newly discovered CARM1/NFIB/TRIM29 signaling axis, and (2) investigate the therapeutic potential of targeting this axis using a battery of pre-clinical mouse models.

抽象的小细胞肺癌（SCLC）患者的治疗选择在30年中一直保持不变， 20年没有新的FDA批准治疗方法，也没有针对性的疗法。我们最近执行了屏幕对于称为CARM1的精氨酸甲基转移酶的靶标，并鉴定了NFI转录因子家族作为此PRMT的底物。重要的是，NFIB拥有肿瘤源性和转移性促进活动 SCLC开发的背景。我们确认CARM1是NFIB的转录共激活因子。基于这些发现，我们假设NFIB的Carm1甲基化对于肿瘤促进至关重要功能。为了进一步支持这个前提 Carm1甲基化位点突变。当该鼠标交叉到SCLC基因工程鼠标上时模型（GEMM）这些小鼠的预期寿命延长了三分之一（200天至300天），几乎是与Carm1-loss在同一宝石中的影响相同。这些发现增加了针对SCLC的可能性带有Carm1小分子抑制剂。我们还确定了CARM1的效应分子（TRIM29） NFIB上的甲基化位点。在此提案中，我们计划：（1）对此新的进行深入的机械分析发现的CARM1/NFIB/TRIM29信号轴，（2）研究靶向的治疗潜力使用一系列临床前鼠标模型的轴。