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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

基本信息

批准号：
10320059
负责人：
Liqin Zhu
金额：
$ 24.67万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320059
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&apos 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 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

项目摘要

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.

项目摘要肝母细胞瘤（HB）是一种罕见的肝癌，仅发生在幼儿中。虽然大多数HB 化疗后肿瘤可以通过手术切除，少数HB患者会复发或转移性疾病，并且它们的存活率很差。由于临床试验有限由于这种癌症的罕见性，需要进行基础研究以了解HB的生物学机制进展和耐药性，以便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），催化脱氧核糖核苷酸形成的酶复合物， DNA复制和修复在高危HB中显著上调。活性RNR复合物是一种由一个大的RNR1亚基和两个小的RNR2亚基之一RRM2构建的异二聚体四聚体或RRM2B。RRM2是分裂细胞中的主要RNR 2亚基，与肿瘤的预后相关。成年人中的许多实体瘤。RRM2B通常在癌细胞中表达较低，但可以在肿瘤细胞中诱导表达。紧张的条件。我们的初步研究表明，RRM2基因的敲低显著抑制了HB细胞的生长，生长，更有趣的是，用标准化疗治疗HB细胞诱导了显著的 RRM2B的上调。在化疗后切除的患者肿瘤中， RRM2B在高风险肿瘤中的表达与低风险肿瘤相比。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 RNR活性促进耐药性。因此，RNR可能是高风险的潜在治疗靶点。和难治性HB。我们建议通过检查开关和特定功能来测试这一假设， RRM2和RRM2B在HB进展和耐药性中的作用，测试现有RRM2抑制剂在在体外和体内与化疗联合，并使用高通量方法筛选药物，可有效降解HB细胞中的RRM2B。该项目的成功将展现RNR的动态复杂的HB发展和适应化疗，并提供科学证据支持 RNR作为高危和难治性HB的新治疗靶点