权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Metabolic Regulation of Glioblastoma Epitranscriptomics

胶质母细胞瘤表观转录组学的代谢调控

基本信息

批准号：
10464413
负责人：
Sameer Agnihotri
金额：
$ 58.93万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-07 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464413
关键词：
Adult Brain Brain Neoplasms Caring Cell Cycle Cell Proliferation Cells Cellular Metabolic Process Chemoresistance Chemotherapy and/or radiation Citric Acid Cycle Clustered Regularly Interspaced Short Palindromic Repeats Collaborations DNA Dasatinib Development Dioxygenases Enzymes Epigenetic Process Event Foundations Genetic Genetic Transcription Glioblastoma Glioma Growth Human Immune Ionizing radiation Isocitrate Dehydrogenase Knock-out Link Maintenance Malate Dehydrogenase Malate-Aspartate Shuttle Pathway Malates Malignant Neoplasms Malignant neoplasm of brain Measures Mediator of activation protein Messenger RNA Metabolic Metabolic Control Metabolism Methylation Mitochondria Modeling Molecular Molecular Target Oncogenic Oxaloacetates Pathway interactions Patients Pharmacodynamics Pharmacology Play Population Post-Transcriptional Regulation Production RNA RNA methylation Radiation therapy Regulation Reporting Research Project Grants Role Therapeutic Therapeutic Intervention Transcript Translating Translations Treatment Failure alpha ketoglutarate angiogenesis base biomarker development cancer stem cell cell growth chemotherapy clinical efficacy clinically relevant conventional therapy demethylation epigenome epitranscriptome epitranscriptomics gain of function histone modification improved in vivo inhibitor loss of function multidisciplinary mutant neoplastic cell new therapeutic target novel novel therapeutics overexpression oxidation palliation palliative chemotherapy patient response patient stratification pre-clinical programs radiation resistance radioresistant response self-renewal small molecule inhibitor standard of care stem stem cell biology stem cell growth stem cells stem-like cell stemness targeted agent targeted treatment therapeutic development therapeutic target therapeutically effective therapy resistant treatment response tumor tumor growth

项目摘要

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.

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。