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

• 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
• 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

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是一种新的有前途的癌症治疗方法。ATR 抑制剂（ATRi）通过在有问题的肿瘤位点引起双链断裂（DSB）而起癌症治疗的作用。 DNA复制。事实上，我们最近已经证明，形成结构的重复DNA序列 强烈影响ATRI驱动的断裂。然而，我们最近的初步研究表明， 结构的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 转录。此外，由于逆转录因子的转录在大多数基因组位置是沉默的，因此它们的转录水平可能会降低。 去阻遏显著增加了由ATRi引起的断裂。 我们假设，癌症相关的改变和沉默抑制剂，促进转录， 倒置的逆向元件将增加对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），表现出许多预期引起增加的特征， 反转录元件的转录。这些改变包括逆转录因子的低甲基化， RB 1和p53介导的重复序列沉默，以及RNASEH 2引起的RNA-DNA杂交的异常加工 缺陷在此，我们建议确定这些前列腺癌相关变化中的每一种如何影响前列腺癌的发生。 ATRi诱导的DNA断裂的位置和数目。此外，我们还将探讨其分子机制 反转录元件转录增加ATRI驱动的选择位点的断裂，并确定 通过临床批准的药物进一步抑制逆转录元件沉默与ATRi协同作用， CRPC小鼠模型中的肿瘤生长。最后，我们将确定这种联合治疗是否更有效。 在ATM、BRCA 2和RB 1的前列腺癌相关突变的背景下有效。总的来说，这些 研究将描述癌细胞对ATRi敏感的新机制， CRPC的联合治疗。