Dual Targeting of Brain Tumor Initiating Cells through Inhibition of BMI1 and EZH2 (R01NS103434)

通过抑制 BMI1 和 EZH2 双重靶向脑肿瘤起始细胞 (R01NS103434)

基本信息

批准号：
10201765
负责人：
JEREMY N RICH
金额：
$ 34.23万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201765
关键词：
Anatomy B-Cell Lymphomas BMI1 gene Biopsy Blood Vessels Brain Glioblastoma Brain Neoplasms Brain Stem Cell Lineage Cells Chromatin Chromatin Remodeling Factor Classification Scheme Clinical Trials Complex Cues Data Dependence Development Dose Enhancers Enzymes Epigenetic Process Gene Expression Profile Gene Expression Profiling Genetic Genetic Transcription Glioblastoma Growth Histologic Histone-Lysine N-Methyltransferase Histones Homologous Gene Human Hypoxia Invaded Link Location Lysine Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Mesenchymal Mesenchymal Cell Neoplasm Messenger RNA Modeling Molecular Neoplasms in Vascular Tissue Normal tissue morphology Organ PRC1 Protein Pathway interactions Patient Selection Patients Pattern Pharmaceutical Preparations Pharmacology Polycomb Population Primary Brain Neoplasms Proteins Radiation Radiation therapy Regimen Regulation Resistance Resources Ring Finger Domain Specimen Stress Therapeutic Toxic effect Transcriptional Activation Translating Tumor Angiogenesis Tumor Stem Cells angiogenesis base cancer cell clinical development clinically relevant conventional therapy epigenetic regulation improved in silico neoplastic cell novel personalized medicine programs protein expression response self-renewal stem stem cells targeted treatment temozolomide therapy resistant tumor tumor heterogeneity tumor hypoxia tumor microenvironment ubiquitin-protein ligase

项目摘要

The most prevalent primary brain tumor, glioblastoma (GBM), ranks among the most lethal of human cancers. Like the normal brain, GBMs contain cellular hierarchies with self-renewing, multi-lineage cells at the apex. These brain tumor initiating cells (BTICs), or GBM stem cells, display therapeutic resistance, promote tumor angiogenesis, and invade into normal tissues. BTICs are not uniformly distributed, but rather concentrated in specific regions, or niches, including around blood vessels (the perivascular niche) and in perinecrotic (hypoxic) regions. These niches provide essential cues that maintain stem-like tumor cells through several pathways that appear specific for each location. In preliminary studies, we find that biopsies of specific GBM regions contain tumor cells with divergent transcriptional profiles and precursor markers. Cellular differentiation states reflect the cumulative regulation of chromatin, so we examined the expression and activity of two core epigenetic regulatory nodes: polycomb repressive complexes 1 and 2 (PRC1/2). Vascular tumor regions were associated with PRC2 activity, whereas hypoxic regions were associated with measures of PRC1. Collectively, these results suggest that stem-like cancer cells residing in different locations may be regulated by different epigenetic programs. Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme that serves as the enzymatic component of PRC2. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) is an essential component of PRC1. Both EZH2 and BMI1 have been linked to normal and neoplastic stem cells, as well as therapeutic resistance. Clinical relevance for BMI1 and EZH2 is supported by the development of targeted therapies against each molecule. We find that mesenchymal BTICs display preferential activity and dependence on BMI1, whereas proneural BTICs display preferential activity and dependence on EZH2. As GBMs contain a mixture of proneural and mesenchymal tumor cells, we hypothesized that combined targeting of BMI1 and EZH2 will offer improved tumor control with acceptable toxicity. Further, we have identified a novel molecular regulatory mechanism of BMI1 linked to the hypoxic microenvironment that may inform patient selection for precision (personalized) medicine application of epigenetic targeting. Finally, additional studies will determine the potential of this therapeutic regimen to synergize with conventional therapies against glioblastoma. Collectively, these studies will investigate novel molecular regulation by the tumor microenvironment of neoplastic stem cells that can be directly translated into clinical trials.

最常见的原发性脑肿瘤，胶质母细胞瘤（GBM），是人类最致命的肿瘤之一癌症。与正常大脑一样，GBM 包含细胞层次结构，其中具有自我更新的多谱系细胞顶点。这些脑肿瘤起始细胞 (BTIC) 或 GBM 干细胞表现出治疗耐药性，促进肿瘤血管生成，并侵入正常组织。 BTIC 并不是均匀分布的，但是相当集中在特定区域或生态位，包括血管周围（血管周围生态位）以及坏死周围（缺氧）区域。这些生态位提供了维持干细胞样肿瘤的重要线索细胞通过多个针对每个位置的特定途径。在初步研究中，我们发现特定 GBM 区域的活检包含具有不同转录谱和前体的肿瘤细胞标记。细胞分化状态反映了染色质的累积调节，因此我们检查了两个核心表观遗传调控节点的表达和活性：多梳抑制复合物 1 和 2 (PRC1/2)。血管肿瘤区域与 PRC2 活性相关，而缺氧区域则与 PRC2 活性相关。与 PRC1 的措施相关。总的来说，这些结果表明干细胞样癌细胞存在于不同位置的基因可能受到不同表观遗传程序的调节。 zeste 同源物 2 (EZH2) 的增强子是一种组蛋白赖氨酸 N-甲基转移酶，充当 PRC2 的酶成分。 B 淋巴瘤 Mo-MLV 插入区 1 同源物 (BMI1) 是必需的 PRC1 的组成部分。 EZH2 和 BMI1 都与正常和肿瘤干细胞相关作为治疗抵抗。 BMI1 和 EZH2 的临床相关性得到以下发展的支持针对每个分子的靶向治疗。我们发现间充质 BTIC 显示出优先活性和对 BMI1 的依赖性，而原神经 BTIC 显示出优先活性和对 BMI1 的依赖性 EZH2。由于 GBM 含有原神经和间充质肿瘤细胞的混合物，我们假设 BMI1 和 EZH2 的联合靶向将改善肿瘤控制并具有可接受的毒性。更远，我们已经确定了 BMI1 与缺氧相关的新型分子调节机制微环境可以帮助患者选择精准（个性化）药物应用表观遗传靶向。最后，其他研究将确定该治疗方案的潜力与针对胶质母细胞瘤的常规疗法具有协同作用。总的来说，这些研究将调查新颖的肿瘤干细胞的肿瘤微环境的分子调节可直接翻译进入临床试验。