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

• 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
• 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

 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（由申请人提供）：小儿脑干胶质瘤是最具破坏性的儿童癌症之一。由于这些肿瘤发生在脑干，因此没有手术选择可以缓解患者的症状，化疗和放疗最多只能提供姑息性缓解。与大多数类型的人类癌症相比，没有显着的 改善脑干胶质瘤患者的治疗结果。直到最近，脑干胶质瘤的治疗缺乏进展，部分原因是很少采集脑干肿瘤组织来分析肿瘤分子特征：直到 2012 年，脑干胶质瘤发生的潜在遗传基础在很大程度上仍然未知。幸运的是，两个研究小组能够通过采集足够数量的脑干肿瘤来进行有意义的突变分析，从而解决这一信息缺陷问题。外显子组测序发现，在多达 60% 的此类肿瘤中，H3F3A 基因反复发生突变，导致编码的组蛋白 H3.3 蛋白中的赖氨酸 27 被蛋氨酸 (K27M) 取代。迄今为止，这种突变对于脑干肿瘤来说仍然是独特且特异的。 K27M 突变导致细胞染色质中组蛋白 H3 K27 甲基化大幅减少，我们最近表明，抑制组蛋白 H3 K27 去甲基化酶 JMJD3 可恢复脑干胶质瘤细胞中的 K27 甲基化，同时在细胞中表现出有效的抗肿瘤活性。 脑干胶质瘤的培养和异种移植模型。这些结果以及其他人发表的结果支持 JMJD3 至少在某些类型的癌症中具有促肿瘤活性。然而，脑干肿瘤中的 K27 甲基化状态很可能受到 JMJD3 之外的活性的影响：有几种调节 K27 甲基化的酶，并且这些活性是否与 JMJD3 协同作用，促进脑干肿瘤的发展，或者相反，反对肿瘤的发展，在很大程度上尚不清楚。该应用将检查不同的 H3 K27 甲基转移酶和去甲基化酶活性如何影响脑干肿瘤生长，从而确定 JMJD3 在肿瘤维持中的作用是否依赖于调节 K27 甲基化的其他蛋白质。此外，该项目还将确定脑干肿瘤如何适应延长的 JMJD3 抑制，这对于确定用于治疗可能对 JMJD3 抑制产生耐药性或可能与 JMJD3 抑制剂联合使用的脑干肿瘤的辅助疗法非常重要。最后，该提案将检查 JMJD3 抑制与辐射结合使用时的效果，因为受 JMJD3 抑制影响的细胞特性之一是 DNA 修复。因此，抑制 JMJD3 可能会增强辐射的细胞毒性作用。