Novel targeted therapy to reduce health disparities in pediatric leukemia
减少儿童白血病健康差异的新型靶向治疗
基本信息
- 批准号:10608229
- 负责人:
- 金额:$ 54.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:5&apos-Nucleotidase6-MercaptopurineAdolescentAffectAffinityAllelesB-Cell Acute Lymphoblastic LeukemiaB-cell precursor acute lymphoblastic leukemia cellBiologicalBiological ModelsChemoresistanceChildChildhood LeukemiaCombined Modality TherapyDNA BindingDNA-Binding ProteinsDataDeath RateExhibitsGene ExpressionGenesGeneticGenetic TranscriptionGrowthHispanicHumanIGH@ gene clusterImpairmentIn VitroIncidenceLatinoLeukemic CellMalignant Childhood NeoplasmMediatingMolecularMutationNot Hispanic or LatinoOncogenicPathway interactionsPharmaceutical PreparationsPharmacotherapyPhosphorylationPhosphotransferasesPopulationPre-Clinical ModelPrognosisPublishingReduce health disparitiesRegulationRelapseRepressionResistanceRoleSignal PathwaySocioeconomic FactorsTestingTherapeutic EffectTranscription RepressorTranscriptional RegulationTreatment EfficacyTumor Suppressor Proteinscancer health disparitycasein kinase IIchemotherapycytotoxicgene repressionhealth disparityhigh riskimprovedin vivoin vivo evaluationinhibitorinsightknock-downleukemialeukemia treatmentnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsoverexpressionpatient derived xenograft modelpediatric patientsprecision medicineresistance mechanismrestorationthiopurinethiopurine methyltransferase
项目摘要
ABSTRACT
Hispanic/Latino (H/L) children and adolescents have a 40% higher death rate than non-Hispanic whites (NHW)
after correcting socioeconomic factors. Recently, we identified a highly increased incidence of deletion of one
IKZF1 allele in H/L children, which provided a biological rationale for the worse prognosis of B-cell acute
lymphoblastic leukemia (B-ALL) in this population. The very high incidence (29%) makes the deletion of one
IKZF1 allele the most frequent genetic alteration that confers adverse prognosis in B-ALL in H/L children. Thus,
understanding the biological basis for resistance to chemotherapy and developing novel therapies to treat B-ALL
with deletion of one IKZF1 allele will reduce the health disparity in survival for Hispanic/Latino children with ALL.
The IKZF1 gene encodes a DNA-binding protein, IKAROS, which functions as a transcriptional regulator. Our
published data showed that, in B-ALL, IKAROS phosphorylation by the oncogenic Casein Kinase II (CK2)
reduces IKAROS DNA-binding affinity and abolishes its function as a transcriptional regulator. Our new
preliminary data suggest that CK2 impairs the ability of IKAROS to repress transcription of two key genes
involved in the thiopurine pathway, resistance to 6-mercaptopurine (6-MP) treatment, and relapse: TPMT and
NT5C2. Treatment with CK2-specific inhibitor, CX-4945, restores IKAROS-mediated repression of the TPMT
and NT5C2 genes in primary B-ALL cells from H/L children. In vitro treatment of B-ALL with CX-4945 in
combination with 6-MP exhibits a strong synergistic cytotoxic effect. Our overall hypothesis is that
overexpression of CK2 in high-risk B-ALL of H/L children impairs IKAROS’ ability to transcriptionally repress the
genes that regulate resistance to treatment with 6-MP, and that CK2 inhibition will restore IKAROS function as
a transcriptional repressor of these genes, resulting in increased sensitivity to 6-MP. This hypothesis will be
tested in vivo, using various biological models. We will define the mechanism through which IKAROS regulates
the thiopurine pathway in primary B-ALL cells from H/L children. The effect of increased CK2 expression on
thiopurine pathway and IKAROS function will be analyzed in patient-derived xenografts (PDXs), generated from
B-ALL from H/L children. Finally, we will establish the therapeutic efficacy of combination treatment with CK2
inhibitor (CX-4945) and 6-mercaptopurine (6-MP) in a preclinical model of B-ALL from H/L children. Results of
the project will provide a novel insight into the regulation of the thiopurine pathway and help develop novel
treatments for high-risk B-ALL in H/L children and reduce childhood cancer health disparities.
摘要
西班牙裔/拉丁裔(H/L)儿童和青少年的死亡率比非西班牙裔白人(NHW)高40%
修正社会经济因素后最近,我们发现了一个高度增加的发生率缺失的一个
IKZF 1等位基因在H/L儿童中的表达,为B细胞急性白血病预后不良提供了生物学依据。
淋巴细胞白血病(B-ALL)。非常高的发生率(29%)使得一个缺失
IKZF 1等位基因是H/L儿童B-ALL中最常见的遗传变异,可导致不良预后。因此,在本发明中,
了解化疗耐药的生物学基础,开发治疗B-ALL的新疗法
一个IKZF 1等位基因的缺失将减少西班牙裔/拉丁裔ALL儿童生存期的健康差异。
IKZF 1基因编码一种DNA结合蛋白IKAROS,其作为转录调节因子发挥作用。我们
已发表的数据显示,在B-ALL中,IKAROS被致癌酪蛋白激酶II(CK 2)磷酸化,
降低IKAROS DNA结合亲和力并消除其作为转录调节因子的功能。我们的新
初步数据表明,CK 2削弱IKAROS抑制两个关键基因转录的能力
参与硫嘌呤途径、对6-巯基嘌呤(6-MP)治疗的耐药性和复发:TPMT和
NT5C2。用CK 2特异性抑制剂CX-4945治疗恢复IKAROS介导的TPMT抑制
和NT 5C 2基因。在体外用CX-4945治疗B-ALL,
与6-MP组合显示出强的协同细胞毒作用。我们的总体假设是
高风险B-ALL的H/L儿童中CK 2的过度表达损害IKAROS转录抑制
调节对6-MP治疗的抗性的基因,并且CK 2抑制将恢复IKAROS功能,
这些基因的转录抑制因子,导致对6-MP的敏感性增加。这一假设将是
使用各种生物模型进行体内测试。我们将定义IKAROS调节的机制
H/L儿童原发性B-ALL细胞中的硫嘌呤途径。CK 2表达增加对
硫嘌呤途径和IKAROS功能将在患者来源的异种移植物(PDX)中进行分析,
B-ALL来自H/L儿童。最后,我们将确定与CK 2联合治疗的疗效。
抑制剂(CX-4945)和6-巯基嘌呤(6-MP)在H/L儿童B-ALL临床前模型中的作用。结果
该项目将提供一个新的洞察硫嘌呤途径的调节,并帮助开发新的
治疗H/L儿童中的高危B-ALL,并减少儿童癌症健康差异。
项目成果
期刊论文数量(0)
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{{ truncateString('Sinisa Dovat', 18)}}的其他基金
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
- 批准号:
10160808 - 财政年份:2017
- 资助金额:
$ 54.1万 - 项目类别:
Targeting CRLF2 and Ikaros Alterations to Reduce Health Disparities in Childhood Leukemia
以 CRLF2 和 Ikaros 改变为目标,减少儿童白血病的健康差异
- 批准号:
9302326 - 财政年份:2016
- 资助金额:
$ 54.1万 - 项目类别:
Targeting CRLF2 and Ikaros Alterations to Reduce Health Disparities in Childhood Leukemia
以 CRLF2 和 Ikaros 改变为目标,减少儿童白血病的健康差异
- 批准号:
9753178 - 财政年份:2016
- 资助金额:
$ 54.1万 - 项目类别:
The Role of Zinc Finger Genes in Leukemogenesis
锌指基因在白血病发生中的作用
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8254521 - 财政年份:2009
- 资助金额:
$ 54.1万 - 项目类别:
The Role of Zinc Finger Genes in Leukemogenesis
锌指基因在白血病发生中的作用
- 批准号:
8296355 - 财政年份:2009
- 资助金额:
$ 54.1万 - 项目类别:
The Role of Zinc Finger Genes in Leukemogenesis
锌指基因在白血病发生中的作用
- 批准号:
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