B55 alpha deficiency as a therapeutic target in cancer

B55 α 缺乏症作为癌症的治疗靶点

• 批准号: 10162546
• 负责人: Junran Zhang
• 金额: $ 35.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10162546
• 关键词: ATR checkpoint; Binding; Biological Assay; Biological Markers; CHEK1 gene; Cancer Etiology; Cancer Patient; Cell Line; Cell Survival; Cell physiology; Cells; Cessation of life; Chromosome Fragile Sites; Clinic; Clinical Trials; DNA Damage; DNA biosynthesis; Data; Dependence; Development; Disease; Epithelial ovarian cancer; Event; Exhibits; Goals; Immune checkpoint inhibitor; Lead; Loss of Heterozygosity; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; Mutate; Mutation; Normal Cell; Normal tissue morphology; Oncogene Activation; Oncogenes; Oncogenic; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Population; Production; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Serine/Threonine Phosphatase; Protein phosphatase; Reactive Oxygen Species; Regulation; Replication Initiation; Reporting; Role; Serous; Signal Transduction; Source; Stratification; Stress; Survival Rate; Testing; Toxic effect; Woman; Xenograft procedure; ataxia telangiectasia mutated protein; base; biological adaptation to stress; c-myc Genes; cancer cell; genome-wide; improved; inhibitor/antagonist; loss of function; mutant; novel; novel marker; novel strategies; patient derived xenograft model; patient population; patient stratification; predict responsiveness; replication stress; response; scaffold; targeted treatment; therapeutic target; therapy resistant; treatment strategy; tumor; tumor growth; whole genome

PROJECT SUMMARY Ovarian cancer is the 5th leading cause of cancer death in women. The overall 5-year survival rate for epithelial ovarian cancer (EOC), the most common type, remains approximately 30% over the last several decades. High- grade serous ovarian cancer (HGSOC) is the most common and lethal form of EOC. Thus, the novel strategies for treating HGSOC are urgently needed. Cancer cells often carry genetic defects that provide opportunities for specific targeting. Expression of the B55 α, a regulatory subunit of the heterotrimeric serine/threonine phosphatase PP2A, is reduced in 46% of ovarian cancers, as a result of loss of heterozygosity. Our recent novel genome-wide synthetic lethality screen discovered that B55 α reduction led to the enhanced sensitivity of cells to an inhibitor targeting replication stress response kinase CHK1. Currently, inhibitors of CHK1 and its upstream effector ATR are being tested in clinical trials without precise guidance of biomarkers to identify responsive populations, which significantly reduce the efficacy of these agents. Thus, the goal of this application is to establish the molecular basis for targeting B55 α defective HGSOC by ATR/CHK1 inhibitors and for B55 α being a biomarker to guide the use of those agents. PP2A has diverse functions, including the negative regulation of numerous oncogenic signaling. Oncogene activation can cause replication stress that could be lethal to the cells. ATR/CHK1 signaling suppresses replication stress to less toxic levels. Thus, cancer cells with increased replication stress, such as cancer cells with c-Myc activation/expression, heavily rely on ATR/CHK1 for survival. Given the role of PP2A in negatively regulating multiple oncogenic pathways, B55 α deficiency may lead to oncogene activation and replication stress, rendering these cells sensitive to ATR/CHK1 inhibition. We hypothesize that ATR and CHK1 inhibitors specifically target B55 α-defective HGSOC cells by enhancing replication stress. Thus, reduced B55 α expression could be a biomarker to guide the use of ATR and CHK1 inhibitors. Three Specific Aims are proposed. In Aim 1, we will determine the role of c-Myc in B55 α deficiency- induced replication stress. In Aim 2, we will determine the causes of the B55 α deficiency-induced replication stress. In Aim 3, we will assess the anti-tumor activities of ATR and CHK1 inhibition in targeting B55 α defective HGSOC cells. If successful, our study will have a significant impact on improving the survival of ovarian cancer patients by identifying new treatment approaches and by providing a new stratification biomarker for identifying ATR/CHK1 inhibitor sensitive populations.

项目摘要 卵巢癌是女性癌症死亡的第五个主要原因。上皮的总体5年生存率 在过去的几十年中，卵巢癌（EOC）是最常见的类型，约有30％。高的- 浆液卵巢癌（HGSOC）是EOC的最常见和致命形式。那是新颖的策略 迫切需要治疗HGSOC。癌细胞经常带有遗传缺陷，为 特定的目标。 B55α的表达，异三个序列/苏氨酸的调节亚基 由于杂合性丧失，磷酸酶PP2A在46％的卵巢癌中降低。我们最近的小说 全基因组综合致死性筛查发现B55α还原导致细胞的灵敏度增强 靶向复制应力反应激酶CHK1的抑制剂。目前，CHK1及其上游的抑制剂 效应子ATR在临床试验中进行了测试，而无需精确指导生物标志物以识别响应能力 种群，大大降低了这些药物的效率。那，该应用程序的目的是 建立靶向ATR/CHK1抑制剂和B55α为B55α缺陷HGSOC的分子基础 一种指导使用这些代理的生物标志物。 PP2A具有不同的功能，包括 许多致癌信号传导。致癌基因激活会导致复制应力，可能对细胞致命。 ATR/CHK1信号传导抑制复制应力降低毒性水平。那，癌细胞增加 复制应激，例如具有C-MYC激活/表达的癌细胞，严重依赖ATR/CHK1来生存。 鉴于PP2A在负调节的多个致癌途径中的作用，B55α缺乏症可能导致 致癌基因激活和复制应力，使这些细胞对ATR/CHK1抑制敏感。我们 假设ATR和CHK1抑制剂特异性地靶向B55α缺陷HGSOC细胞 复制应力。那就是降低的B55α表达可能是指导ATR和CHK1使用的生物标志物 抑制剂。提出了三个具体目标。在AIM 1中，我们将确定C-MYC在B55α缺乏症中的作用 - 诱导复制应力。在AIM 2中，我们将确定B55α缺乏诱导的复制的原因 压力。在AIM 3中，我们将评估靶向B55α有缺陷的ATR和CHK1抑制的抗肿瘤活性 HGSOC细胞。如果成功，我们的研究将对改善卵巢癌的生存产生重大影响 通过识别新的治疗方法并提供新的分层生物标志物来识别患者 ATR/CHK1抑制剂敏感人群。