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

基本信息

批准号：
9302326
负责人：
Sinisa Dovat
金额：
$ 36.05万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302326
关键词：
Acute Lymphocytic Leukemia Affect Alleles B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Cell Cycle Cell Proliferation Cell Survival Cells Cessation of life Child Childhood Childhood Leukemia Combined Modality Therapy Cytokine Receptors Data Death Rate Defect Disease Progression Engineering Epigenetic Process FRAP1 gene Gene Expression Genes Genetic Hispanics Human Ikaros protein Immune Impairment Injectable JAK2 gene Knowledge Latino Ligands Malignant Childhood Neoplasm Measures Molecular Mus Mutation Not Hispanic or Latino Oncogenic PI3 gene PI3K/AKT Pathway interactions Patients Pharmacotherapy Phosphotransferases Pre-Clinical Model Process Proto-Oncogene Proteins c-akt Relapse Repression Role Sampling Serum Sirolimus Stat5 protein TSLP gene Testing Therapeutic Therapeutic Effect Time Treatment Efficacy Tumor Suppressor Proteins Xenograft Model Xenograft procedure base cancer health disparity disease mechanisms study health disparity high risk in vivo inhibitor/antagonist leukemia mTOR Inhibitor mTOR Signaling Pathway mTOR inhibition mortality new therapeutic target novel novel therapeutics overexpression pediatric patients precision medicine preclinical study receptor restoration

项目摘要

SUMMARY Hispanic children are more likely to develop acute lymphocytic leukemia (ALL), and when this occurs they are 39% more likely to die than non-Hispanic Whites. This disparity is due, in part, to a subtype of B-cell precursor ALL (B-ALL) that occurs five times more frequently among Hispanic children than others and has a high relapse rate. This type of leukemia, called CRLF2 B-ALL, is characterized by two genetic alterations: a) overexpression of the cytokine receptor, CRLF2, and b) deletion or inactivation of one allele of the Ikaros (IKZF1) tumor suppressor which is strongly associated with relapse. Our overall hypothesis is that combination therapy that selectively targets the pathways that are deregulated in CRLF2 B-ALL (CRLF2 and Ikaros) will produce a superior therapeutic effect and decrease mortality to reduce the health disparity in survival for Hispanic children with ALL. When the CRLF2 receptor is activated by its ligand, TSLP, downstream pathways (JAK/STAT and PI3/AKT/mTOR) that promote leukemia cell survival, proliferation, and chemoresistance are induced through processes normally kept in check by the Ikaros tumor suppressor. Preliminary data from our team show that treatment with the CK2-specific inhibitor, CX-4945, restores Ikaros tumor suppressor function in high-risk B-ALL from Hispanic patients with deletion of one Ikaros allele, exerting a strong in vivo therapeutic effect. Preclinical studies of CRLF2 B-ALL typically use patient-derived xenograft (PDX) models, where primary leukemia cells from patients with CRLF2 B-ALL are injected into immune deficient mice. Our preliminary data show that mouse TSLP does not activate human CRLF2, making the current PDX models suboptimal for studies of CRLF2 B-ALL. To overcome this obstacle our team engineered immune deficient mice that provide normal human serum levels of human TSLP (+T mice) and generated PDX by injecting these mice with CRLF2 B-ALL cells from Hispanic pediatric patients (+T PDX). Analysis of +T PDX shows CRLF2 activation and gene expression that is more similar to original patient sample than standard PDX. Our preliminary data provide a rationale for novel therapy that targets pathways that are induced by CRLF2 (JAK-STAT5 and PI3K/AKT/mTOR) and by loss of Ikaros tumor suppressor activity using our newly- developed preclinical model for Hispanic CRLF2 B-ALL. To test our hypothesis we will: Aim 1: Establish the in vivo therapeutic efficacy of targeting CRLF2 downstream pathways and their role in CRLF2 B-ALL in Hispanic pediatric patients. Aim 2: Evaluate the in vivo efficacy and mechanisms of combination therapy that restores Ikaros tumor suppressor activity and inhibits the mTOR pathway in Hispanic pediatric CRLF2 B-ALL. The proposed studies use precision medicine approaches (targeting specific pathways and/or functional defects) in context of the health disparity background to develop a novel treatment for CRLF2 B-ALL and reduce childhood cancer health disparities.

概括西班牙裔儿童更有可能患上急性淋巴细胞白血病 (ALL)，当这种情况发生时，他们死亡可能性比非西班牙裔白人高 39%，这种差异部分是由于 B 细胞前体亚型造成的。 ALL (B-ALL) 在西班牙裔儿童中发生的频率是其他儿童的五倍，并且发病率很高这种类型的白血病称为 CRLF2 B-ALL，具有两种基因改变的特征：a) 细胞因子受体 CRLF2 的过度表达，以及 b) Ikaros 的一个等位基因的缺失或失活（IKZF1）肿瘤抑制因子与复发密切相关。我们的总体假设是：联合疗法选择性地针对 CRLF2 B-ALL 中失调的通路（CRLF2 和 Ikaros）将产生卓越的治疗效果并降低死亡率，从而缩小健康差距当 CRLF2 受体被其下游配体 TSLP 激活时，患有 ALL 的西班牙裔儿童的生存率。促进白血病细胞存活、增殖和增殖的途径（JAK/STAT 和 PI3/AKT/mTOR）化疗耐药性是通过通常由 Ikaros 肿瘤抑制因子控制的过程诱导的。我们团队的初步数据显示，使用 CK2 特异性抑制剂 CX-4945 治疗可恢复 Ikaros 缺失一个 Ikaros 等位基因的西班牙裔高危 B-ALL 患者中的肿瘤抑制功能 CRLF2 B-ALL 的临床前研究通常使用患者来源的异种移植物。 (PDX) 模型，将来自 CRLF2 B-ALL 患者的原代白血病细胞注射到免疫细胞中我们的初步数据表明，小鼠 TSLP 不会激活人类 CRLF2，从而使目前的 PDX 模型对于 CRLF2 B-ALL 的研究来说不是最佳的。为了克服这个障碍，我们的团队设计了。免疫缺陷小鼠，提供正常人血清水平的人类 TSLP（+T 小鼠）并生成 PDX 通过向这些小鼠注射来自西班牙裔儿科患者的 CRLF2 B-ALL 细胞 (+T PDX)。显示 CRLF2 激活和基因表达与原始患者样本比标准更相似我们的初步数据为针对 PDX 诱导途径的新疗法提供了理论基础。 CRLF2（JAK-STAT5 和 PI3K/AKT/mTOR）以及使用我们新推出的 Ikaros 肿瘤抑制活性的丧失开发了西班牙裔 CRLF2 B-ALL 的临床前模型为了检验我们的假设，我们将：目标 1：建立模型。靶向 CRLF2 下游治疗途径的体内功效及其在西班牙裔 CRLF2 B-ALL 中的作用目标 2：评估联合治疗的体内疗效和恢复机制。 Ikaros 肿瘤抑制活性并抑制西班牙裔儿童 CRLF2 B-ALL 中的 mTOR 通路。拟议的研究使用精准医学方法（针对特定途径和/或功能缺陷）健康差异背景下开发一种新的 CRLF2 B-ALL 治疗方法并减少儿童癌症健康差异。