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.

项目概要抑制 DNA 复制检查点调节剂 ATR 是一种新的、有前途的癌症治疗方法。衰减全反射抑制剂（ATRi）通过在有问题的位点引起双链断裂（DSB）来起到癌症治疗的作用 DNA复制。事实上，我们最近已经证明，结构形成重复 DNA 序列对 ATRi 驱动的破损有很大影响。然而，我们最近的初步研究表明，异常DNA 结构形成并不是这些地点脆弱性的唯一决定因素。我们现在已经证明 ATRi- 反向逆向元件重复序列的驱动断裂受到促进其恢复的治疗的强烈刺激转录。此外，由于逆转录元件的转录在大多数基因组位置被沉默，它们的去抑制会显着增加 ATRi 引起的破损。我们假设与癌症相关的改变和沉默抑制剂促进了转录倒置逆转录元件将增加对 ATRi 治疗的敏感性。重要的是，晚期前列腺癌，大多数特别是去势抵抗性前列腺癌（CRPC），表现出许多预计会导致增加的特征反向逆转录因子的转录。这些改变包括逆转录因子的低甲基化、 RB1和p53介导的重复沉默，以及RNA酶H2导致的RNA-DNA杂交体的异常加工不足。在此，我们建议确定这些与前列腺癌相关的变化如何影响 ATRi 诱导的 DNA 断裂的定位和数量。此外，我们还将探讨其分子机制反向逆转录元件转录会增加选定位点 ATRi 驱动的断裂，并确定是否通过临床批准的药物进一步抑制逆转录元件沉默可与 ATRi 协同作用以抑制 CRPC 小鼠模型中肿瘤的生长。最后，我们将确定这种联合治疗是否更有效对前列腺癌相关的 ATM、BRCA2 和 RB1 突变有效。总的来说，这些研究将描述癌细胞对 ATRi 敏感的新机制，并确定新的机制 CRPC 的联合治疗。