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

通过抑制 BMI1 和 EZH2 双重靶向脑肿瘤起始细胞

• 批准号: 9398480
• 负责人: JEREMY N RICH
• 金额: $ 33.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398480
• 关键词: Anatomy; B-Cell Lymphomas; BMI1 gene; Biopsy; Blood Vessels; Brain Glioblastoma; Brain Neoplasms; Brain Stem; Brain Stem Neoplasms; Cells; Chromatin; Classification Scheme; Clinical Trials; Complex; Computer Simulation; Cues; Data; Dependence; Development; Dose; Enhancers; Enzymes; Epigenetic Process; 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; Stem cells; Stress; Therapeutic; Toxic effect; Transcriptional Activation; Translating; Tumor Angiogenesis; Tumor Initiators; Tumor Stem Cells; angiogenesis; base; cancer cell; clinical development; clinically relevant; conventional therapy; epigenetic regulation; improved; neoplastic cell; novel; personalized medicine; profiles in patients; programs; protein expression; response; self-renewal; stem; targeted treatment; temozolomide; therapy resistant; tumor; tumor heterogeneity; 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），是人类最致命的人之一 癌症。像正常的大脑一样，GBM包含具有自我更新的多段细胞的细胞层次结构 顶点。这些脑肿瘤引发细胞（BTICS）或GBM干细胞表现出治疗性抗性， 促进肿瘤血管生成，并侵入正常组织。 btics不是均匀分布的，而是 相当集中于特定区域或壁ni，包括血管周围（血管周围的小裂） 以及核酸（低氧）区域。这些利基提供了维持茎状肿瘤的必需线索 细胞通过几个对每个位置特定的途径。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曲线和前体的肿瘤细胞 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节节点的表达和活性：Polycomb抑制性复合物1和2 （PRC1/2）。血管肿瘤区域与PRC2活性有关，而低氧区域为 与PRC1的度量相关。总的来说，这些结果表明居住的茎状癌细胞 在不同的位置，可以通过不同的表观遗传程序来调节。 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，用作 PRC2的酶促成分。 B淋巴瘤MO-MLV插入区域1同源物（BMI1）是必不可少的 PRC1的组成部分。 EZH2和BMI1都与正常和肿瘤干细胞有关 作为治疗性抗性。 BMI1和EZH2的临床相关性得到了发展的支持 针对每个分子的靶向疗法。我们发现间充质btics显示优先活动 以及对BMI1的依赖性，而胸膜btics则表现出优先活动和依赖性 EZH2。由于GBM含有隆起和间充质肿瘤细胞的混合物，我们假设 BMI1和EZH2的联合靶向将提供可接受的毒性控制的改善肿瘤控制。更远， 我们已经确定了与低氧有关的BMI1的新型分子调节机制 微环境可能会告知患者选择精确（个性化）医学的应用 表观遗传靶向。最后，其他研究将确定这种治疗方案的潜力 与针对胶质母细胞瘤的常规疗法协同作用。这些研究集体研究了新颖 可以直接翻译的肿瘤细胞的肿瘤微环境调节分子调节 进入临床试验。