Therapeutic targeting of demethylation-deubiquitination axis in acute leukemia

急性白血病去甲基化-去泛素化轴的治疗靶向

基本信息

批准号：
10133024
负责人：
Panagiotis Ntziachristos
金额：
$ 36.41万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133024
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Acute leukemia Adolescent Animals Binding Biological Availability Cell Cycle Cell Death Cell Line Cells Cellular biology Chemicals Chemoresistance Chemotherapy and/or radiation Child Childhood Acute Lymphocytic Leukemia Chromatin Clinic Clinical Complex Coupled DNA Sequence Alteration Data Deubiquitination Diagnosis Diagnostic Disease Disease model Disease-Free Survival Environment Epigenetic Process Exhibits Face Fellowship Foundations Future Gene Expression Genetic Transcription Genomics Growth Hematopoietic Neoplasms Histones Human Immunotherapy In Vitro Incidence Individual Infiltration Investigational Therapies Knockout Mice Laboratories Lead Leukemic Cell Life Light Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Manuscripts Medicine Modeling Molecular Molecular Profiling Molecular Target Mus Mutation NOTCH1 gene Nature Oncogenes Oncogenic Outcome Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacology Phenotype Physiological Post-Translational Protein Processing Postdoctoral Fellow Pre-Clinical Model Preparation Process Prognosis Proteins Proteomics Publishing Recurrent disease Refractory Refractory Disease Regimen Relapse Research Residual Neoplasm Resistance Risk Role Sampling Second Primary Cancers Solid T-Cell Leukemia Tertiary Protein Structure Testing Therapeutic Tissues Toxic effect Toxicology Ubiquitin Ubiquitination Xenograft Model Xenograft procedure acute lymphoblastic leukemia cell aggressive therapy anticancer research cancer diagnosis cell growth chemoradiation chemotherapy demethylation disorder risk drug development drug discovery engineered T cells genome sequencing high risk human model in vivo inhibitor/antagonist leukemia malignant state mouse model new therapeutic target novel patient derived xenograft model pre-clinical programs research study resistance mechanism response small molecule small molecule inhibitor targeted treatment therapeutic target therapy resistant tool transcription factor tumor tumor growth whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with high unmet needs, as high cure rates achieved with intensive chemoradiation come at the expense of high toxicity rates and risk of secondary malignancies. Still, up to 25% pediatric ALL patients fail or relapse post-frontline chemoradiation, while response rates for relapsed disease are dismal (~20%). Whole-genome sequencing capabilities have shed new light on oncogenic processes, but identifying “clean” targets remain elusive (easily druggable proteins, dysregulated in cancer but not in healthy cells). We hypothesize that oncogenic transformation is driven by aberrant activity of oncogene-associated chromatin (epigenetic) modifying partners. These changes create a chromatin environment unique to the malignant state. Our preliminary data, including the ones published in Clinical Cancer Research, provides strong evidence that two chromatin oncogenic partners in ALL, JMJD3, an epigenetic player coopted by oncogenes such as NOTCH1, and the deubiquitinase USP7, represent novel therapeutic targets in T-ALL. USP7 appears to control tumor growth and JMJD3 and NOTCH1 stabilization is at least one potential mechanism. Inhibition of each of JMJD3 and USP7 using small molecules appears to significantly inhibit growth of leukemia cells in vitro. We propose to further characterize the pro-oncogenic roles of JMJD3 and USP7 in relevant human and murine models, model USP7 mutations in cancer and conduct preclinical analyses of small molecule inhibitors against these two targets (used as single agents or in combinations). Other mechanistic studies will include a proteomic screen for USP7 interactors and global histone changes. We will evaluate study genomic and chemical inhibition of JMJD3 and USP7 (individual and combined), in human T-ALL lines, primary patient samples, and mouse:human xenograft disease models with respect to: 1) transcriptional and epigenetic changes, 2) cellular viability, and 3) animal survival. Absent any targeted therapies currently in use for T cell ALL, identification of two novel targets for inhibitor cocktails could provide a useful concept for future drug development. Our biopharma collaborators have already generated chemical inhibitors for both JMJD3 and USP7. We anticipate our mechanistic analyses could serve as solid foundation for future toxicology analyses, along with further chemical optimization.

项目摘要/摘要急性淋巴细胞白血病（ALL）是一种具有高未满足需求的侵略性血液癌，因为较高的治愈率通过强化化学放疗实现的代价为高毒性率和次要的风险恶性。尽管如此，最多25％的小儿所有患者失败或转电后化学放疗，而反应继电器疾病的比率很沮丧（约20％）。全基因组测序功能已经开发了新的启示致癌过程，但是识别“清洁”靶标仍然难以捉摸（易于吸毒的蛋白质，失调癌症，但不在健康细胞中）。我们假设致癌转化是由癌基因相关染色质的异常活性驱动的（表观遗传）修改伴侣。这些变化创造了恶性状态独有的染色质环境。我们的初步数据，包括在临床癌症研究中发表的数据，提供了有力的证据表明总共两个染色质致癌伙伴JMJD3，这是一个由notch1等癌基因构成的表观遗传参与者，去泛素酶USP7代表T-All中的新型治疗靶标。 USP7似乎控制肿瘤生长和JMJD3和Notch1稳定至少是一种潜在的机制。抑制JMJD3 使用小分子的USP7似乎在体外显着抑制白血病细胞的生长。我们建议进一步表征JMJD3和USP7在相关的人和鼠中的亲构作用模型，建模癌症中的USP7突变，并对针对小分子抑制剂进行临床前分析这两个目标（用作单个代理或组合）。其他机械研究将包括蛋白质组学 USP7互动器和全球Hisstone的屏幕变化。我们将在人类中评估研究JMJD3和USP7的基因组和化学抑制（个人和联合） T-ALL线，主要的患者样品和小鼠：相对于：1）转录和表观遗传变化，2）细胞活力和3）动物存活。没有目前用于T细胞的任何靶向疗法，鉴定两个新型抑制剂靶标鸡尾酒可以为未来的药物开发提供有用的概念。我们的生物制药合作者已经 JMJD3和USP7产生的化学抑制剂。我们预计我们的机械分析可以服务作为未来毒理学分析的坚实基础，以及进一步的化学优化。