Effect of DNA repeat silencing on efficacy of ATRi in prostate cancer treatment

DNA重复序列沉默对ATRi治疗前列腺癌疗效的影响

基本信息

批准号：
10658509
负责人：
Eric J Brown
金额：
$ 46.14万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2023-04-03 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658509
关键词：
ATM Gene Mutation Affect BRCA2 gene CDC2 gene Cell Line Clinical Combined Modality Therapy Complex Cyclin A DNA DNA Double Strand Break DNA Polymerase III DNA Replication Inhibition DNA Sequence DNA Structure DNA Synthesis Inhibition DNA biosynthesis DNA replication fork Defect Double Strand Break Repair Drug Synergism Etiology Exhibits Fostering Frequencies Gene Silencing Generations Genetic Predisposition to Disease Genetic Transcription Genome Genomics Histones Hybrids Location Malignant Neoplasms Malignant neoplasm of prostate Mediating Methylation Minisatellite Repeats Molecular Multienzyme Complexes Mutation Pharmaceutical Preparations Play Prostate Cancer therapy RB1 gene RNA RNA Processing Repetitive Sequence Retroelements Role Short Interspersed Nucleotide Elements Site Structure Sulfamethoxazole TP53 gene Testing Therapeutic advanced prostate cancer cancer cell cancer therapy castration resistant prostate cancer derepression efficacy testing endonuclease experimental study genomic locus inhibitor mouse model novel premature prostate cancer cell synergism treatment strategy tumor tumor growth

项目摘要

PROJECT SUMMARY Inhibition of the DNA replication checkpoint regulator ATR is a new and promising cancer treatment. ATR inhibitors (ATRi) function as cancer treatments by causing double-stranded breaks (DSBs) at sites of problematic DNA replication. Indeed, we have recently demonstrated that structure-forming repetitive DNA sequences strongly influence on ATRi-driven breakage. However, our recent preliminary studies indicate that abnormal DNA structure formation is not the sole determinant of vulnerability at these sites. We have now shown that ATRi- driven breakage at inverted retroelement repeats is strongly stimulated by treatments that promote their transcription. Moreover, because the transcription of retroelements is silenced at most genomic locations, their derepression substantially increases breakage caused by ATRi. We hypothesize that cancer-associated alterations and silencing inhibitors that foster the transcription of inverted retroelements will increase sensitivity to ATRi treatment. Importantly, advanced prostate cancer, most notably castration-resistant prostate cancer (CRPC), exhibits many features expected to cause increased transcription of inverted retroelements. These alterations include the hypomethylation of retroelements, the loss of RB1 and p53-mediated repeat silencing, and the abnormal processing of RNA-DNA hybrids due to RNASEH2 deficiency. Herein, we propose to determine how each of these prostate cancer-associated changes affect the localization and number of DNA breaks induced by ATRi. Furthermore, we will explore the molecular mechanism by which inverted retroelement transcription increases ATRi-driven breakage at select sites and determine if further inhibition of retroelement silencing by clinically approved drugs synergizes with ATRi to suppress the growth of tumors in mouse models of CRPC. Finally, we will determine if this combination treatment is more effective in the context of prostate cancer-associated mutation of ATM, BRCA2 and RB1. Collectively, these studies will characterize new mechanisms by which cancer cells are sensitized to ATRi as well as identify novel combination treatments for CRPC.

项目摘要抑制DNA复制检查点调节剂ATR是一种新的且有希望的癌症治疗方法。 Atr 抑制剂（ATRI）通过在有问题的部位引起双链休息（DSB）作为癌症治疗 DNA复制。确实，我们最近证明了结构形成重复的DNA序列对ATRI驱动的破裂有强烈影响。但是，我们最近的初步研究表明异常DNA 结构形成不是这些位点脆弱性的唯一决定因素。我们现在已经表明了在倒立的倒元重复序列时驱动的断裂受到促进其促进其的治疗的强烈刺激转录。此外，由于大多数基因组位置都沉默了追溯元素的转录，因此压缩大大增加了由ATRI引起的破裂。我们假设与癌症相关的改变和沉默抑制剂促进了转录倒的逆转元素将增加对ATRI治疗的敏感性。重要的是，晚期前列腺癌，大多数明显的cast割前列腺癌（CRPC）表现出许多预期会导致增加的特征倒的倒元素转录。这些变化包括重新元素的甲基化，损失 RB1和p53介导的重复沉默，以及由于RNAseH2而引起的RNA-DNA杂交的异常处理不足。本文中，我们建议确定这些前列腺癌相关的每一个都如何影响 ATRI诱导的DNA断裂的定位和数量。此外，我们将探索分子机制倒逆转录转录会增加某些地点的ATRI驱动破裂，并确定是否是否进一步抑制临床认可的药物与ATRI协同抑制的追溯沉默以抑制 CRPC小鼠模型中肿瘤的生长。最后，我们将确定这种组合处理是否更多在ATM，BRCA2和RB1的前列腺癌相关突变的背景下有效。总的来说，这些研究将表征癌细胞对ATRI敏感并识别新机制的新机制 CRPC的组合处理。