Deve inlopment of A High-Throughput Screen for Identification of Targeted Therapies in Brainstem Tumors with the H3K27M Mutation

开发用于鉴定 H3K27M 突变脑干肿瘤靶向治疗的高通量筛选

• 批准号: 10192036
• 负责人: David Daniels
• 金额: $ 89.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192036
• 关键词: Acetylation; Affect; Amino Acids; Antineoplastic Agents; Biological; Biological Assay; Biological Markers; Brain; Brain Neoplasms; Brain Stem Neoplasms; CRISPR/Cas technology; Cell Line; Cell Maintenance; Cell Survival; Cells; Cessation of life; Chemicals; Child; Childhood Glioma; Childhood Malignant Brain Tumor; Clinical Trials; Data; Diagnosis; Diffuse; Diffuse intrinsic pontine glioma; Disease; Diversity Library; Dose; Drug Screening; Enhancers; Ensure; Epigenetic Process; Gene Expression; Gene Silencing; Genes; Glioma; Goals; H3 K27M mutation; Heterogeneity; Histone H3; Image; Immunofluorescence Immunologic; Lead; Libraries; Link; Longevity; Lysine; Malignant Neoplasms; Methionine; Methylation; Morphologic artifacts; Mutation; Names; Normal Cell; Pathologic; Patients; Pediatric Neoplasm; Performance; Pharmaceutical Preparations; Phase; Play; Primary Brain Neoplasms; Reproducibility; Research; Role; Somatic Mutation; Specificity; Testing; Therapeutic Agents; Toxic effect; Validation; Vision; anti-cancer; base; cancer cell; cancer therapy; design; drug repurposing; epigenome; glioma cell line; high throughput screening; innovation; methylation pattern; neoplastic cell; novel; novel therapeutics; palliative; pediatric patients; response; screening; small molecule; stem cell differentiation; success; synergism; targeted treatment; tool; tumor; tumorigenesis

PROJECT SUMMARY Pediatric high-grade gliomas including Diffuse Intrinsic Pontine Gliomas (DIPG) are aggressive brain tumors that occur in children. The lifespan for these patients after diagnosis is about one year with no cure in sight. Countless clinical trials have been performed without success and treatment remains palliative despite extensive research over the past decade. It is therefore critical to identify new therapies for these deadly diseases. Among pediatric patients, one of the most devastating brain tumor types is diffuse midline gliomas with the H3K27M mutation, which includes the previously named Diffuse Intrinsic Pontine Glioma (DIPG). Recently, somatic mutations in the H3F3A gene, one of the 16 genes that encode Histone H3, have been detected in the majority of high-grade pediatric glioma cases including DIPG. This mutation leads to an amino acid change at lysine (K) 27 residue of H3.3 to methionine (M). The H3K27M mutation is a striking example of a genetic alteration that drives tumorigenesis by modifying the epigenome. H3K27 is modified post- translationally by either acetylation or methylation. H3K27 trimethylation (H3K27me3) plays an important role in gene silencing during stem cell differentiation and maintenance. The major pathologic finding in H3K27M tumors is a global loss of H3K27me3. The changes in H3 Lysine methylation patterns dramatically change gene expression and are likely to function as drivers of malignancy in these tumors. Our goal is to develop new therapies for treating children with H3K27M tumors by developing a toolbox of primary and secondary assays and to identify small molecule compounds that increase the suppressed H3K27me3 levels in tumors with the H3K27M mutation. Our preliminary data along with others show increasing H3K27me3 leads to tumor death in H3K27M mutant tumors. Building on these exciting results we hypothesize that a disease-relevant high- throughput screening (HTS) assay can be developed and executed leading to novel therapeutic agents for brainstem tumors with the H3K27M mutation.

项目摘要 儿童高级别胶质瘤包括弥漫性内在脑桥胶质瘤（DIPG）是侵袭性脑肿瘤 发生在儿童身上。这些患者在确诊后的寿命约为一年，目前还没有治愈的迹象。 无数的临床试验都没有成功，尽管如此，治疗仍然是姑息性的。 在过去十年中进行了广泛的研究。因此，确定这些致命的新疗法至关重要。 疾病在儿科患者中，最具破坏性的脑肿瘤类型之一是弥漫性中线胶质瘤 H3 K27 M突变，包括以前命名的弥漫性内在脑桥胶质瘤（DIPG）。 最近，编码组蛋白H3的16个基因之一的H3 F3 A基因的体细胞突变已经被发现。 在包括DIPG在内的大多数高级别儿童胶质瘤病例中检测到。这种突变导致了一种氨基 H3.3的赖氨酸（K）27残基变为甲硫氨酸（M）。H3 K27 M突变是一个引人注目的例子， 一种通过改变表观基因组来驱动肿瘤发生的基因改变。H3 K27是在 通过乙酰化或甲基化反应。H3 K27三甲基化（H3 K27 me 3）在合成中起重要作用。 干细胞分化和维持过程中的基因沉默。H3 K27 M的主要病理改变 肿瘤是H3 K27 me 3的整体丢失。H3赖氨酸甲基化模式的变化 基因表达，并可能在这些肿瘤中作为恶性肿瘤的驱动因素。我们的目标是开发新的 通过开发初级和次级检测工具箱治疗H3 K27 M肿瘤儿童的疗法 并鉴定增加肿瘤中抑制的H3 K27 me 3水平的小分子化合物， H3 K27 M突变。我们与其他人的初步数据沿着显示，H3 K27 me 3的增加导致肿瘤死亡。 H3 K27 M突变型肿瘤。基于这些令人兴奋的结果，我们假设一种疾病相关的高- 可以开发和执行通量筛选（HTS）测定，从而产生用于治疗癌症的新型治疗剂。 脑干肿瘤H3 K27 M突变