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.

项目概要/摘要急性淋巴细胞白血病 (ALL) 是一种侵袭性血癌，由于治愈率高，其需求未得到满足通过强化放化疗实现的效果是以高毒性率和继发性风险为代价的。尽管如此，仍有高达 25% 的儿童 ALL 患者在一线放化疗后失败或复发，而治疗效果却良好。疾病复发率很低（约 20%），全基因组测序能力为这一问题提供了新的线索。致癌过程，但识别“干净”的目标仍然难以捉摸（容易药物化的蛋白质，在癌症但不在健康细胞中）。我们认为致癌转化是由致癌基因相关染色质的异常活性驱动的（表观遗传）修饰伙伴。这些变化创造了恶性状态特有的染色质环境。我们的初步数据，包括发表在《临床癌症研究》上的数据，提供了强有力的证据： ALL 中的两个染色质致癌伙伴 JMJD3，是一个与 NOTCH1 等致癌基因共同参与的表观遗传因子，和去泛素酶 USP7，代表了 T-ALL 的新治疗靶点，USP7 似乎可以控制肿瘤。 JMJD3 的生长以及 JMJD3 和 NOTCH1 的稳定至少是抑制 JMJD3 的一种潜在机制。使用小分子的 USP7 似乎可以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 在相关人类和小鼠中的促癌作用模型，对癌症中的 USP7 突变进行建模，并对小分子抑制剂进行临床前分析这两个目标（作为单一药物或组合使用）将包括蛋白质组学。 USP7 相互作用子和全局组蛋白变化的筛选。我们将评估人类中 JMJD3 和 USP7（单独和组合）的基因组和化学抑制研究 T-ALL 系、主要患者样本和小鼠：人类异种移植疾病模型涉及：1) 转录和表观遗传变化，2) 细胞活力，3) 动物存活。目前没有任何针对 T 细胞 ALL 的靶向疗法，确定了两个新的抑制剂靶点鸡尾酒可以为未来的药物开发提供有用的概念。我们预计我们的机制分析可以用于 JMJD3 和 USP7 的化学生成抑制剂。作为未来毒理学分析以及进一步化学优化的坚实基础。