Targeting histone demethylase activity for the treatment of pediatric brainstem glioma

靶向组蛋白去甲基化酶活性治疗儿童脑干胶质瘤

基本信息

批准号：
9308024
负责人：
Rintaro Hashizume
金额：
$ 30.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308024
关键词：
7 year old Acute T Cell Leukemia Address Affect Animals Apoptosis Apoptotic Biological Biological Process Brain Stem Brain Stem Glioma Brain Stem Neoplasms Brain region Cancer Patient Cell Culture Techniques Cell Proliferation Cells ChIP-seq Characteristics Child Childhood Chromatin Chronic Combined Modality Therapy Complementary DNA DNA Double Strand Break DNA Repair DNA-Binding Proteins Development Diffuse intrinsic pontine glioma Diploid Cells Effectiveness Enzymes Gene Mutation Genes Genetic Glioma Goals Histone H3 Histones Human Incidence Individual Lead Length Lysine Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of brain Methionine Methylation Methyltransferase Modality Molecular Molecular Biology Molecular Profiling Mus Mutation Mutation Analysis Nature Oncogenic Operative Surgical Procedures Patients Peptides Pharmacology Positioning Attribute Property Proteins Publishing Radiation Radiation enhancer Radiation therapy Recurrence Research Resistance Role Small Interfering RNA Symptoms Testing Therapeutic Time Transcript Treatment Protocols Treatment outcome Tumor Tissue Tumorigenicity Variant Work Xenograft Model Xenograft procedure antitumor effect base cancer recurrence cancer type chemotherapy cytotoxic demethylation enzyme activity exome sequencing experience genetic analysis histone demethylase histone methylation in vivo inhibitor/antagonist interest migration mutant neoplastic cell novel outcome forecast palliative public health relevance radiation effect repaired response small hairpin RNA small molecule inhibitor therapeutic target transcriptome sequencing tumor tumor growth tumor xenograft tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Pediatric brainstem glioma is among the most devastating childhood cancers. Since these tumors occur in the brainstem, there are no surgical options for providing relief to patients, and chemotherapy as well as radiation therapy provide palliative relief at best. In contrast to most types of human cancer, there has been no significant improvement in treatment outcomes for brainstem glioma patients. Until recently, the lack of improvement for treating brainstem glioma was attributable, in part, to infrequent brainstem tumor tissue acquisition for analyzing tumor molecular characteristics: the underlying genetic basis for brainstem glioma occurrence remained largely unknown, until as recently as 2012. Fortunately, two groups were able to address this information deficiency by acquiring sufficient numbers of brainstem tumors to conduct meaningful mutation analysis. Exome sequencing identified recurrent mutation of the H3F3A gene, resulting in replacement of lysine 27 by methionine (K27M) in the encoded histone H3.3 protein, in as many as 60% of these tumors. To date, this mutation remains unique and specific to brainstem tumors. The K27M mutation causes substantial reduction in histone H3 K27 methylation in cellular chromatin, and we have recently shown that inhibition of the histone H3 K27 demethylase JMJD3 acts to restore K27 methylation in brainstem glioma cells, while demonstrating potent anti-tumor activity, both in cell culture and in xenograft models of brainstem glioma. These results, as well as results published by others, support JMJD3 as having pro-tumorigenic activity in at least some types of cancer. However, it is likely that K27 methylation status in brainstem tumors is influenced by activities i addition to JMJD3: there are several enzymes that regulate K27 methylation, and whether these activities act in concert with JMJD3, to promote brainstem tumor development, or, alternatively, oppose tumor development, is largely unknown. This application will examine how different H3 K27 methyltransferase and demethylase activities influence brainstem tumor growth, and in so doing will determine whether JMJD3's role in tumor maintenance is dependent upon other proteins that regulate K27 methylation. This project will, in addition, determine how brainstem tumors adapt to extended JMJD3 inhibition, which is important for identifying secondary therapeutics to use in treating brainstem tumors that may acquire resistance to JMJD3 inhibition, or that could potentially be used in combination with JMJD3 inhibitors. Finally, this proposal will examine the effects of JMJD3 inhibition when used in combination with radiation, as one of the cellular properties affected by JMJD3 inhibition is DNA repair. JMJD3 inhibition, therefore, may enhance the cytotoxic effects of radiation.

描述（由申请人证明）：m，没有外科手术可以缓解患者，化学疗法以及放射疗法palliatide palliatide palliatide palliative at at toct toct and palliatide palliatigy palliative at at toct。脑干神经胶质瘤的改善结果。获取足够数量的脑干进行有意义的突变分析（在编码的H3.3蛋白中，多达60％的肿瘤中的K27M。最近表明，在脑干神经胶质瘤细胞中，组蛋白H3 K27脱甲基酶K27甲基化的吸收均在细胞中，均在细胞中在至少某些类型的癌症中，这些结果C活性很可能是在脑干肿瘤中受到JMJD3的影响，在脑干肿瘤中可能会有几种调节K27甲基化的酶，脑干肿瘤的发展，或替代性肿瘤的发育是更大的未知数。 D JMJD3对识别疗法的使用很重要，可能会使用JMJD3抑制剂来获得对JMJD3的耐药性。