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Targeting CK2 oncogenic pathway to overcome drug resistance in high-risk leukemia

靶向CK2致癌途径克服高危白血病耐药性

基本信息

批准号：
10160808
负责人：
Sinisa Dovat
金额：
$ 35.39万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160808
关键词：
Affinity Alleles Apoptosis Apoptotic B-Cell Acute Lymphoblastic Leukemia B-cell precursor acute lymphoblastic leukemia cell BCL1 Oncogene Catalytic Domain Cell Proliferation Childhood Clinical Research Combined Modality Therapy DNA Binding DNA-Binding Proteins Data Development Dihydrofolate Reductase Disease Disease model Doxorubicin Drug resistance Exhibits Folic Acid Folic Acid Antagonists Genes Genetic Genetic Transcription Homocysteine S-methyltransferase Impairment In Vitro Mediating Methotrexate Molecular NADPH Dehydrogenase Oncogenic Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Pre-Clinical Model Prognosis Publishing Regulation Repression Resistance Role TYMS gene Testing Therapeutic Therapeutic Effect Thymidylate Synthase Transcription Repressor Treatment Efficacy Tumor Suppression Tumor Suppressor Proteins base carbene casein kinase II cell growth regulation cellular transduction chemotherapy cytotoxic cytotoxicity design effectiveness testing folic acid metabolism high risk in vivo in vivo evaluation inhibitor/antagonist insight leukemia leukemogenesis novel novel drug combination overexpression patient derived xenograft model pediatric patients protein function targeted treatment therapy design treatment strategy

项目摘要

SUMMARY The Ikaros (IKZF1) gene encodes a DNA-binding protein that functions as a tumor suppressor and a transcriptional regulator in leukemia. Deletion of one Ikaros allele results in the development of high-risk B-cell acute lymphoblastic leukemia (B-ALL) that is resistant to chemotherapy and has a poor prognosis. Our recently published data show that CK2 (Casein Kinase II), an oncogenic kinase that is overexpressed in B-ALL, phosphorylates Ikaros, which reduces Ikaros DNA-binding affinity and abolishes its activity as a transcriptional regulator. Based on these findings we designed a novel B-ALL treatment strategy to restore Ikaros function by targeting CK2. The inhibition of CK2 with a specific inhibitor, CX-4945, as a single drug, restored Ikaros ability to regulate transcription in high-risk B-ALL with deletion of one Ikaros allele and showed therapeutic efficacy in a preclinical model of this disease. Our new preliminary data suggest that CK2 impairs the ability of Ikaros to repress transcription of genes essential to the folic acid metabolism pathway: MTHFD1 (methylene- tetrahydrofolate dehydrogenase NADP+ dependent 1), MTR (5-methyltetrahydrofolate-homocysteine methyl- transferase) and TYMS (Thymidylate Synthase), as well as the anti-apoptotic gene, BCL-XL. In leukemia, high expression of the folic acid pathway genes and BCL-XL are associated with increased resistance to methotrexate and doxorubicin treatment, respectively. Treatment with the CK2-specific inhibitor, CX-4945, restored Ikaros-mediated repression of the MTHFD1, MTR, TYMS and BCL-XL genes in primary high-risk B- ALL cells. In vitro treatment of high-risk B-ALL with CX-4945 in combination with methotrexate, or doxorubicin exhibits a strong synergistic cytotoxicity. We hypothesize that overexpression of CK2 in high-risk B-ALL impairs Ikaros ability to transcriptionally repress the folic acid pathway and Bcl-XL genes and that CK2 inhibition will restore Ikaros tumor suppressor activity as a transcriptional repressor of these genes in high-risk B-ALL cells resulting in increased sensitivity to methotrexate and doxorubicin treatment. We will test this hypothesis in vivo, using patient-derived xenografts (PDX) from pediatric patients with high-risk B- ALL in the following specific aims: In Aim 1, we will establish the therapeutic efficacy of combination treatment with the CK2 inhibitor (CX-4945) and the folic acid pathway inhibitor (methotrexate) in a preclinical model of high-risk B-ALL and determine the molecular mechanisms that restore Ikaros ability to repress folic acid pathway genes. In Aim 2, we will evaluate the in vivo efficacy of combination therapy with CX-4945 and doxorubicin and analyze the mechanism that restores Ikaros–mediated repression of BCL-XL in high-risk B-ALL. In Aim 3, we will identify the mechanisms through which high expression of CK2 regulates drug resistance and Ikaros tumor suppressor function in B-ALL. Results of the proposed project would establish the therapeutic efficacy of two novel combination treatments for high-risk B-ALL and provide mechanistic insights into the regulation of tumor suppression in pediatric high-risk B-ALL.

总结 Ikaros（IKZF 1）基因编码一种DNA结合蛋白，其功能是肿瘤抑制因子和肿瘤抑制因子。白血病中的转录调节因子。一个Ikaros等位基因的缺失导致高危B细胞急性淋巴细胞白血病（B-ALL），对化疗有抗性，预后不良。我们最近公开的数据显示CK 2（酪蛋白激酶II），一种在B-ALL中过表达的致癌激酶，磷酸化Ikaros，这降低了Ikaros DNA结合亲和力，并消除了其作为转录因子的活性。调节器基于这些发现，我们设计了一种新的B-ALL治疗策略，通过以下方式恢复Ikaros功能：针对CK 2。用特异性抑制剂CX-4945作为单一药物抑制CK 2，恢复了Ikaros的能力，在一个Ikaros等位基因缺失的高危B-ALL中调节转录，并在这种疾病的临床前模型。我们新的初步数据表明，CK 2损害了Ikaros的能力，抑制叶酸代谢途径必需基因的转录：MTHFD 1（亚甲基- 四氢叶酸脱氢酶NADP+依赖性1），MTR（5-甲基四氢叶酸-高半胱氨酸甲基- 转移酶）和TYMS（胸苷酸合酶），以及抗凋亡基因BCL-XL。在白血病中，叶酸途径基因和BCL-XL的表达与对叶酸的抗性增加有关。甲氨蝶呤和阿霉素治疗。用CK 2特异性抑制剂CX-4945治疗，在原发性高风险B- 所有细胞。CX-4945联合甲氨蝶呤或阿霉素体外治疗高危B-ALL 表现出很强的协同细胞毒性。我们假设高危B-ALL中CK 2的过度表达削弱了Ikaros转录抑制叶酸途径和Bcl-XL基因的能力，抑制将恢复Ikaros肿瘤抑制活性，作为这些基因的转录阻遏物，高危B-ALL细胞导致对甲氨蝶呤和阿霉素治疗的敏感性增加。我们将使用来自高危B-淋巴瘤儿科患者的患者源性异种移植物（PDX）在体内检验这一假设。 ALL在以下具体目标中：在目标1中，我们将确定联合治疗的疗效。用CK 2抑制剂（CX-4945）和叶酸途径抑制剂（甲氨蝶呤）治疗，高风险B-ALL的临床前模型，并确定恢复Ikaros能力的分子机制，抑制叶酸途径基因。在目标2中，我们将评估联合治疗的体内功效与CX-4945和阿霉素，并分析恢复Ikaros介导的抑制的机制，高风险B-ALL中的BCL-XL。在目标3中，我们将确定高表达的 CK 2调节B-ALL的耐药性和Ikaros肿瘤抑制功能。拟议预算的结果该项目将确定两种新型联合治疗高风险B-ALL的疗效，为儿科高危B-ALL的肿瘤抑制调节提供了机制性见解。