Metabolic Regulation of Glioblastoma Epitranscriptomics

摘要 胶质母细胞瘤是所有人类癌症中最致命的。目前的标准治疗 患有胶质母细胞瘤的患者只能提供姑息治疗。治疗失败的原因有很多， 包括存在干细胞样肿瘤细胞，称为胶质母细胞瘤干细胞（GSC）。全球供应链有助于 放射抗性、化学抗性、侵袭、免疫逃逸和血管生成。此前，我们曾报道， 在甲基供体代谢和甲基利用的关键节点中， 在胶质母细胞瘤中过度表达的通路。靶向甲基供体代谢 表达减少了GSC的细胞增殖、自我更新和体内肿瘤生长。因此，甲基供体 代谢是胶质母细胞瘤中有希望的GSC特异性治疗靶点， 致癌DNA低甲基化。在初步研究中，我们已经扩大了我们的努力， 胶质母细胞瘤中的重编程，通过调节表转录组学来维持干性， 鉴定在GSC中优先具有活性的代谢和分子靶标。利用以下组合 遗传和药理学抑制剂，我们已经确定了关键的监管机构，表现为改变 表位转录组甲基化事件以维持GSC。 在拟议的研究中，我们将询问选定的代谢酶的功能贡献， 致癌代谢物的产生和肿瘤细胞状态的重编程以维持干性。我们将 通过GSC中产生或丢失的代谢物研究细胞状态的代谢控制，然后 定义负责的特定分子调节因子，包括对干性介质的关注。初步 研究中，我们发现GSC中代谢的改变诱导了转录后调控的改变， 使RNA谱向干样状态转变的mRNA。我们现在试图了解代谢和 这些观察结果背后的表观转录调节因子，以确定高度 恶性肿瘤细胞群，并支持更好的治疗干预措施的发展。此外，委员会认为， 表观转录组学可作为选定靶向治疗剂的药效学量度， 靶向代谢调节表观遗传调节剂。 为了将这些努力转化为新的临床前范例，我们正在使用靶向 代谢靶点和表转录组学。这些小分子抑制剂可以潜在地与 其他疗法来创建胶质母细胞瘤的治疗范例。以产生最有效的治疗方法 模型，我们将询问新的靶向治疗的临床前效用，破坏代谢和 表观遗传重编程，有可能加强常规治疗的疗效。统称 拟议的研究将为更好地理解癌症中的代谢重编程奠定基础。 干细胞生物学与可能的翻译，以改善肿瘤护理。

ABSTRACT Glioblastomas rank among the most lethal of all human cancers. Current standard-of-care therapy for patients afflicted with glioblastoma offers only palliation. Treatment failure derives from numerous causes, including the presence of stem-like tumor cells, called glioblastoma stem cells (GSCs). GSCs contribute to radioresistance, chemoresistance, invasion, immune escape, and angiogenesis. Previously, we reported that critical nodes in methyl donor metabolism and methyl utilization ranked among the most consistently overexpressed pathways in glioblastoma relative to normal brain. Targeting methyl donor metabolism expression reduced cellular proliferation, self-renewal, and in vivo tumor growth of GSCs. Thus, methyl donor metabolism is a promising GSC-specific therapeutic target in glioblastoma that would result in disrupting oncogenic DNA hypomethylation. In preliminary studies, we have extended our efforts to bridge metabolic reprogramming in glioblastoma with maintenance of stemness through regulation of epitranscriptomics to identify metabolic and molecular targets that are preferentially active in GSCs. Leveraging a combination of genetic and pharmacologic inhibitors, we have identified key regulators that manifests as altered epitranscriptomic methylation events to maintain GSCs. In the proposed studies, we will interrogate the functional contributions of selected metabolic enzymes in oncogenic metabolite production and reprogramming of the tumor cell state to maintain stemness. We will investigate the metabolic control of cell state through the metabolites generated or lost in GSCs and then define the specific molecular regulators responsible, including a focus on stemness mediators. In preliminary studies, we find that altered metabolism in GSCs induces alterations in the post-transcriptional regulation of mRNAs that shift the RNA profiles towards a stem-like state. We now seek to understand the metabolic and epitranscriptional regulator underlying these observations to determine the molecular regulation of highly malignant tumor cell populations and support the development of better therapeutic interventions. Moreover, epitranscriptomics may serve as a pharmacodynamic measure of selected targeted therapeutics and that target metabolically regulated epigenetic modulators. To translate these efforts into proof-of-principle novel preclinical paradigms, we are using agents that target metabolic targets and epitranscriptomics. These small molecule inhibitors can potentially be combined with other therapies to create therapeutic paradigms for glioblastoma. To generate the most effective therapeutic model, we will interrogate the preclinical utility of novel targeted therapies that disrupt the metabolic and epigenetic reprogramming with potential to accentuate the efficacy of conventional therapy. Collectively, the proposed studies will lay the foundation for improved understanding of metabolic reprogramming in cancer stem cell biology with possible translation to improved oncologic care.