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。当前的护理标准疗法患有胶质母细胞瘤的患者仅提供抑制。治疗失败来自许多原因，包括存在称为胶质母细胞瘤干细胞（GSC）的干肿瘤细胞的存在。 GSC贡献了放射线，化学抗性，侵袭，免疫逃生和血管生成。以前，我们报告了甲基供体代谢和甲基利用率中的关键节点排名最稳定胶质母细胞瘤相对于正常脑的过表达途径。靶向甲基代谢表达降低了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有希望的GSC特异性治疗靶标，会导致破坏致癌DNA降压甲基化。在初步研究中，我们扩大了弥合代谢的努力通过调节表面转录组学对胶质母细胞瘤进行重新编程，以维持干性确定在GSC中优先活跃的代谢和分子靶标。利用遗传和药理学抑制剂，我们已经确定了表现为改变的关键调节剂表面参考甲基化事件以维持GSC。在拟议的研究中，我们将询问选定代谢酶在中的功能贡献肿瘤细胞态的致癌代谢产物生产和重编程以保持干性。我们将通过在GSC中产生或丢失的代谢物研究细胞态的代谢控制，然后定义负责的特定分子调节剂，包括关注干性介质。在初步研究，我们发现GSC中新陈代谢的改变会引起转录后调节的改变将RNA曲线转移到类似干状态的mRNA。我们现在寻求了解代谢和这些观察结果的表达调节剂，以确定高度的分子调节恶性肿瘤细胞群体并支持更好的治疗干预措施的发展。而且，表十一章可以用作选定靶向治疗剂的药效学指标，并且目标代谢调节的表观遗传调节剂。为了将这些努力转化为原则新颖的新型临床前范式，我们正在使用针对的代理代谢靶标和表面参考组学。这些小分子抑制剂可能与为胶质母细胞瘤创建治疗范例的其他疗法。产生最有效的治疗模型，我们将询问破坏代谢和代谢的新型靶向疗法的临床前实用性表观遗传重编程，有可能突出常规疗法的功效。集体，拟议的研究将奠定基础，以改善对癌症代谢重编程的理解干细胞生物学，可能翻译以改善肿瘤护理。