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

最常见的原发脑瘤，胶质母细胞瘤(GBM)，是人类最致命的肿瘤之一 癌症。像正常大脑一样，基底膜含有细胞层次结构，具有自我更新的多谱系细胞。 顶峰。这些脑肿瘤启动细胞(BTIC)，或GBM干细胞，显示出治疗耐药性， 促进肿瘤血管生成，并侵袭正常组织。BTIC不是均匀分布的，但是 而是集中在特定的区域或壁龛，包括血管周围(血管周围壁龛) 在坏死区(缺氧区)。这些壁龛提供了维持干细胞样肿瘤的基本线索。 细胞通过几条似乎特定于每个位置的路径。在初步研究中，我们发现 特定GBM区域的活检含有具有不同转录特征和前体的肿瘤细胞 记号笔。细胞分化状态反映了染色质的累积调节，因此我们研究了 两个核心表观遗传调控节点：多梳抑制复合体1和2的表达和活性 (PRC1/2)。血管肿瘤区域与PRC2活性相关，而缺氧区与PRC2活性相关 与PRC1的衡量标准相关联。总而言之，这些结果表明，干细胞样癌细胞 在不同的位置可能受到不同的表观遗传程序的调控。 Zust同源增强子2(EZH2)是一种组蛋白赖氨酸N-甲基转移酶，它是一种组蛋白赖氨酸N-甲基转移酶。 PrC2的酶组分。B淋巴瘤Mo-MLV插入区1同源基因(BMI1)是一种必不可少的 PRC1的组件。EZH2和BMI1都与正常干细胞和肿瘤干细胞有关 作为治疗抵抗力。BMI1和EZH2的临床相关性得到以下研究的支持 针对每个分子的靶向治疗。我们发现间充质BTIC表现出优先的活性。 和对BMI1的依赖，而原神经BTICs表现出对BMI1的优先活性和依赖 EZH2.由于基底膜含有神经和间充质肿瘤细胞的混合物，我们假设 联合靶向BMI1和EZH2将提供更好的肿瘤控制和可接受的毒性。此外， 我们发现了BMI1与缺氧相关的一种新的分子调控机制 可通知患者选择精准(个性化)药物应用的微环境 表观遗传靶向。最后，更多的研究将确定这种治疗方案的潜力 与传统疗法协同对抗胶质母细胞瘤。总的来说，这些研究将调查小说 肿瘤微环境对肿瘤干细胞可直接翻译的分子调控 进入临床试验。

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.