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：
10661590
负责人：
Sameer Agnihotri
金额：
$ 58.11万
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/10661590
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 Invaded Ionizing radiation Isocitrate Dehydrogenase Knock-out Link Maintenance Malate Dehydrogenase Malate-Aspartate Shuttle Pathway Malates Malignant Neoplasms Malignant neoplasm of brain Measures Mediator Messenger RNA Metabolic Metabolic Control Metabolism Methylation Mitochondria Modeling Molecular Molecular Target Oncogenic Oxaloacetates Pathway interactions Patients Pharmacodynamics 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 biomarker development cancer stem cell cell growth chemotherapy clinical efficacy clinically relevant cofactor conventional therapy demethylation epigenome epitranscriptome epitranscriptomics gain of function histone modification improved in vivo inhibitor kinase inhibitor loss of function multidisciplinary mutant neoplastic cell new therapeutic target novel novel therapeutics overexpression oxidation palliation palliative chemotherapy patient response patient stratification pharmacologic 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 synergism 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.

抽象的胶质母细胞瘤是所有人类癌症中最致命的一种。目前的标准护理治疗患有胶质母细胞瘤的患者只能起到缓解作用。治疗失败的原因有很多，包括干细胞样肿瘤细胞的存在，称为胶质母细胞瘤干细胞（GSC）。 GSC 有助于放射抗性、化学抗性、侵袭、免疫逃逸和血管生成。此前，我们曾报道过甲基供体代谢和甲基利用的关键节点排名最一致相对于正常大脑，胶质母细胞瘤中过度表达的通路。靶向甲基供体代谢表达降低了 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一个有前途的 GSC 特异性治疗靶点，它会导致破坏致癌DNA低甲基化。在初步研究中，我们扩大了努力以桥接代谢胶质母细胞瘤中的重编程通过表观转录组学的调节来维持干性识别 GSC 中优先活跃的代谢和分子靶标。综合利用遗传和药物抑制剂，我们已经确定了关键的调节因子，这些调节因子表现为改变表观转录组甲基化事件以维持 GSC。在拟议的研究中，我们将探讨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，然后定义负责的具体分子调节因子，包括关注干性调节因子。在初步研究中，我们发现 GSC 代谢的改变会导致转录后调控的改变将 RNA 谱转变为茎状状态的 mRNA。我们现在寻求了解新陈代谢和表观转录调节剂是这些观察结果的基础，以确定高度的分子调节恶性肿瘤细胞群并支持开发更好的治疗干预措施。而且，表观转录组学可以作为选定靶向治疗药物的药效学测量，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理验证的新型临床前范例，我们正在使用针对代谢目标和表观转录组学。这些小分子抑制剂有可能与其他疗法为胶质母细胞瘤创造治疗范例。产生最有效的治疗模型中，我们将探讨破坏代谢和代谢的新型靶向疗法的临床前效用。表观遗传重编程有可能增强传统疗法的疗效。总的来说，拟议的研究将为加深对癌症代谢重编程的理解奠定基础干细胞生物学可能转化为改善肿瘤护理。