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)

• 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
• 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

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.

最普遍的原发性脑肿瘤，胶质母细胞瘤（GBM），是人类最致命的肿瘤之一。 癌的像正常的大脑一样，GBM包含具有自我更新的多谱系细胞的细胞层次， 顶点。这些脑肿瘤起始细胞（BTIC）或GBM干细胞显示出治疗抗性， 促进肿瘤血管生成，并侵入正常组织。BTIC不是均匀分布的，但 而是集中在特定区域或小生境，包括血管周围（血管周围小生境） 和在围坏死（缺氧）区域中。这些小生境提供了维持干细胞样肿瘤的基本线索， 细胞通过几个途径，似乎具体为每个位置。初步研究发现， 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，因此我们检测了 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PRC 2活性相关，而缺氧区域与PRC 2活性相关。 与PRC 1的措施相关。总的来说，这些结果表明， 在不同的位置可能受到不同的表观遗传程序的调节。 zeste增强子同源物2（EZH 2）是一种组蛋白-赖氨酸N-甲基转移酶， PRC 2的酶组分。B淋巴瘤Mo-MLV插入区1同源物（BMI 1）是一种重要的免疫调节因子， PRC 1的组成部分。EZH 2和BMI 1都与正常和肿瘤干细胞有关， 作为治疗抵抗。BMI 1和EZH 2的临床相关性得到了以下研究的支持： 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， 和依赖于BMI 1，而前神经BTIC显示优先活动和依赖于 EZH2.由于GBM含有前神经和间叶肿瘤细胞的混合物，我们假设， BMI 1和EZH 2的组合靶向将提供具有可接受毒性的改善的肿瘤控制。此外，本发明还 我们已经确定了一种新的与低氧相关的BMI 1分子调节机制， 微环境，可以告知患者选择精确（个性化）药物应用， 表观遗传靶向最后，进一步的研究将确定这种治疗方案的潜力， 与常规疗法协同对抗胶质母细胞瘤。总的来说，这些研究将调查新的 肿瘤干细胞的肿瘤微环境的分子调控，可以直接翻译 临床试验