Metabolic Regulation of Glioblastoma Epitranscriptomics

摘要 胶质母细胞瘤是人类所有癌症中最致命的癌症之一。目前的护理标准疗法 患有胶质母细胞瘤的患者只能得到缓解。治疗失败的原因很多， 包括干细胞样肿瘤细胞的存在，称为胶质母细胞瘤干细胞(GSCs)。GSC有助于 辐射抵抗、化学抵抗、侵袭、免疫逃逸和血管生成。此前，我们曾报道过 甲基供体代谢和甲基利用的关键节点是最一致的 胶质母细胞瘤相对于正常脑的过度表达途径。靶向甲基供体代谢 表达抑制了GSCs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有希望的GSC特异性治疗靶点，将导致干扰 致癌DNA低甲基化。在初步研究中，我们已经扩展了我们在新陈代谢方面的努力 胶质母细胞瘤中通过调节表位转录来维持干性的重新编程 确定GSC中优先活跃的代谢和分子靶点。利用以下各项的组合 遗传和药物抑制，我们已经确定了表现为改变的关键调节因子 维持GSCs的表位转录甲基化事件。 在拟议的研究中，我们将询问选定的代谢酶在 致癌代谢物的产生和肿瘤细胞状态的重新编程以维持干性。我们会 通过在GSCs中产生或丢失的代谢物，研究细胞状态的代谢控制 确定负责的特定分子调节剂，包括重点关注茎干调节剂。在预赛中 研究发现，GSCs中代谢的改变会导致转录后调控的改变 使RNA图谱向茎状状态转变的mRNAs。我们现在试图理解新陈代谢和 这些观察结果背后的表位转录调控因子决定了高度的分子调控 这将有助于减少恶性肿瘤细胞的数量，并支持制定更好的治疗干预措施。此外， 表位转录物可以作为选定的靶向治疗的药效学措施，并且 靶向代谢调节的表观遗传调节剂。 为了将这些努力转化为原则证明的新的临床前范例，我们正在使用针对 代谢靶点和表位转录组学。这些小分子抑制剂可以潜在地与 为胶质母细胞瘤创造治疗范例的其他疗法。以产生最有效的治疗方法 模型，我们将询问新型靶向疗法的临床前效用，这些疗法扰乱新陈代谢和 表观遗传学重新编程，有可能加强传统疗法的疗效。总体而言， 拟议的研究将为更好地理解癌症中的代谢重新编程奠定基础 干细胞生物学，可能转化为改进的肿瘤学护理。

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.