Ribonucleotide Reductase in Hepatoblastoma Progression and Drug Resistance

核糖核苷酸还原酶在肝母细胞瘤进展和耐药性中的作用

• 批准号: 10112404
• 负责人: Liqin Zhu
• 金额: $ 20.98万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112404
• 关键词: Accounting; Adult; Basic Science; Binding; Biological; Biology; Cell Cycle; Cell Cycle Progression; Cell Survival; Cell division; Cells; Child; Childhood; Clinical Trials; Collection; Complex; DNA Repair; DNA biosynthesis; Deoxyribonucleotides; Development; Disease; Drug Screening; Drug resistance; Excision; Financial Support; Growth; Hepatic; Hepatoblastoma; In Vitro; Incidence; Intention; International; Knock-out; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of liver; Mammals; Modeling; Molecular Target; Mus; Neonatal; Neoplasm Metastasis; Operative Surgical Procedures; Organoids; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Process; Production; Prognosis; Proteins; RNR1 gene; RRM1 gene; RRM2 gene; Rare Diseases; Recurrence; Recurrent tumor; Refractory; Regulation; Research; Resected; Ribonucleotide Reductase; Ribonucleotide Reductase Inhibitor; Ribonucleotides; Risk; Role; Saint Jude Children' s Research Hospital; Sampling; Signal Pathway; Solid Neoplasm; Testing; TimeLine; United States National Institutes of Health; Unresectable; Up-Regulation; Very Low Birth Weight Infant; anticancer research; base; cancer cell; cancer drug resistance; cell growth; chemotherapy; drug testing; effective therapy; efficacy testing; high risk; high-throughput drug screening; improved; in vivo; inhibitor/antagonist; knock-down; new therapeutic target; novel; overexpression; patient derived xenograft model; rare cancer; replication stress; response; scaffold; skills; standard care; success; synergism; targeted agent; therapeutic target; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY Hepatoblastoma (HB) is a rare liver cancer that occurs exclusively in young children. Although most HB tumors can be removed by surgery after chemotherapy, a small number of HB patients do develop recurrent or metastatic disease following standard treatment and their survival is poor. Since clinical trials are limited due to the rareness of this cancer, basic research is needed to understand the biology responsible for HB progression and drug resistance in order to develop more effective treatment. Our recent study found ribonucleotide reductase (RNR), an enzymatic complex catalyzing the formation of deoxyribonucleotides for DNA replication and repair, is significantly upregulated in high-risk HB. The active RNR complex is a heterodimeric tetramer constructed by a large RNR1 subunit and one of the two small RNR2 subunits, RRM2 or RRM2B. RRM2 is the dominant RNR2 subunit in dividing cells and is associated with the prognosis of many solid tumors in adults. RRM2B is expressed low in cancer cells in general but can be induced under stressful conditions. Our preliminary study showed that RRM2 knockdown significantly inhibited HB cell growth, and more interestingly, treating HB cells with standard chemotherapy induced a significant upregulation of RRM2B. In patient tumors removed after chemotherapy, there was also a much higher level of RRM2B in the high-risk tumors compared to the low-risk tumors. Thus, we hypothesize that the subunit switching from RRM2 to RRM2B during chemotherapy is a key mechanism through which HB cells retain RNR activity to promote drug resistance. Therefore, RNR can be a potential therapeutic target for high-risk and refractory HB. We propose to test this hypothesis by examining the switching and specific function of RRM2 and RRM2B in HB progression and drug resistance, testing the efficacy of existing RRM2 inhibitors in combination with chemotherapy in vitro and in vivo, and use a high-throughput approach to screen drugs that can effectively degrade RRM2B in HB cells. The success of this project will unfold the dynamics of RNR complex during HB development and adaption to chemotherapy, and provide scientific evidence supporting RNR as a new therapeutic target for high-risk and refractory HB.

项目总结 肝母细胞瘤(HB)是一种罕见的肝癌，仅发生在幼儿。尽管大多数Hb 化疗后可以通过手术切除肿瘤，少数乙肝患者确实会复发 或标准治疗后的转移性疾病，他们的存活率很低。由于临床试验有限 由于这种癌症非常罕见，需要进行基础研究来了解导致乙肝的生物学因素。 进展和耐药性，以开发更有效的治疗方法。我们最近的研究发现 核糖核苷酸还原酶(RNR)，一种催化合成脱氧核糖核苷酸的酶复合体 DNA复制和修复，在高危乙肝中显著上调。活性RNR络合物是一种 由一个大的RNR1亚基和两个小的RNR2亚基之一RRM2组成的异二聚体四聚体 或RRM2B。RRM2是细胞分裂中主要的RNR2亚基，与卵巢癌的预后有关 成人的许多实体瘤。RRM2B通常在癌细胞中低表达，但可以在 压力很大的环境。我们的初步研究表明，RRM2基因敲除显著抑制了HB细胞 生长，更有趣的是，用标准化疗治疗HB细胞诱导了显著的 RRM2B上调。在化疗后切除的患者肿瘤中，也有更高水平的 RRM2B在高危肿瘤中与低危肿瘤相比。因此，我们假设亚基 在化疗期间从RRM2转换为RRM2B是HB细胞保留的关键机制 RnR活性促进耐药。因此，RNR可成为高危人群潜在的治疗靶点。 和难治性Hb。我们建议通过检查开关和特定的功能来检验这一假设 RRM2和RRM2B在HB进展和耐药性中的作用，测试现有RRM2抑制剂在HB进展和耐药性中的疗效 与体外和体内化疗相结合，并使用高通量方法筛选 能有效降解HB细胞中的RRM2B。该项目的成功将揭示RNR的动态 在乙肝的发展和对化疗的适应过程中的复杂性，并提供科学证据支持 RnR可作为高危难治性HB的新治疗靶点。