Cellular Plasticity and equilibrium in GBM Progression

GBM 进展中的细胞可塑性和平衡

• 批准号: 10539645
• 负责人: Atique U. Ahmed
• 金额: $ 44.27万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539645
• 关键词: Address; Anabolism; Attention; Blood; Brain; Cancer Patient; Cell Proliferation; Cells; ChIP-seq; Chemoresistance; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Combined Modality Therapy; Complex; DNA; DNA Damage; DNA Repair; DNA biosynthesis; Data; Disease Progression; Engraftment; Enzymes; Epigenetic Process; Equilibrium; Family; Funding; Genome; Glioblastoma; Goals; Guanine; Heterogeneity; Human; In Vitro; Individual; Inter-tumoral heterogeneity; Isotope Labeling; Isotopes; Knock-out; Knowledge; Legal patent; Measures; Mediating; Metabolic; Modification; Molecular; Mus; Nucleotides; Oxidoreductase; Pathway interactions; Patients; Permeability; Pre-Clinical Model; Primary Brain Neoplasms; Primary Neoplasm; Process; Production; Protein Isoforms; Purines; RRM1 gene; Radio; Recurrence; Regulation; Research; Resistance; Ribonucleotide Reductase; Ribonucleotide Reductase Subunit; Safety; Sampling; Stress; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Triapine; base; cancer stem cell; cell growth; chemotherapy; deoxyguanosine triphosphate; epigenetic regulation; experimental study; improved outcome; in vivo; inhibitor; insight; nanodrug; neoplastic cell; novel; novel strategies; patient derived xenograft model; prevent; resistance mechanism; response; single cell analysis; single-cell RNA sequencing; stem cell population; stem-like cell; temozolomide; therapy resistant; treatment response; tripolyphosphate; tumor

PROJECT SUMMARY To advance our understanding of therapeutic resistance in Glioblastoma (GBM), it is essential to characterize the individual cell during therapy those fuel tumor recurrence in GBM. However, it is challenging to study the GBM during conventional radio- and chemotherapy due to limited accessibility to patient samples during this time period. Our lab performed a single-cell RNA sequencing screen in the patient-derived xenograft model of GBM during temozolomide (TMZ) therapy. Our analysis revealed that the Ribonucleotide Reductase Regulatory Subunit 2 (RRM2) mediates deoxynucleoside triphosphates (dNTPs) production necessary for proper DNA replication stable cell growth, promotes metabolic adaptation to TMZ therapy, and initiate recurrence. We have identified a novel mechanism where RRM2-mediated dCTP and dGTP can enhance the DNA repair in response to TMZ and promotes resistance to therapy. Based on this, we hypothesize that RRM2-mediated RNR activity is critical for chemoresistance in GBM. To investigate this hypothesis, we intend to elucidate the RNR-mediated chemoresistance in GBM (Aim 1). Next, we will evaluate a blood-brain permeable RRM2 inhibitor to prevent RNR-mediated chemoresistance in GBM (Aim 2). We established collaboration with Nanopharmaceutic, which holds the patent for producing clinical-grade 3-AP and will provide us with clinical-grade 3-AP to test its efficacy further and advance our understanding of the mechanism of action by which it can be used to treat GBM patients. Finally, we intend to investigate the mechanism of therapeutic resistance by specific nucleotides produced by the RRM2-mediated de novo pathway (Aim 3). Collectively, our studies will provide novel insights regarding changes in dNTP synthesis that are associated with GBM adaptation and resistance during chemotherapy. This information, in turn, is expected to reveal novel approaches for delaying, if not preventing, tumor recurrence.

项目摘要 为了提高我们对胶质母细胞瘤（GBM）治疗耐药性的理解， 治疗期间的单个细胞会导致GBM中的肿瘤复发。然而，研究 常规放疗和化疗期间的GBM，因为在此期间患者样本的可及性有限 时间段我们的实验室进行了单细胞RNA测序筛选在患者来源的异种移植模型， 替莫唑胺（TMZ）治疗期间的GBM。我们的分析表明，核糖核苷酸还原酶调节 亚基2（RRM 2）介导正确DNA所必需的脱氧核苷三磷酸（dNTPs）的产生 复制稳定细胞生长，促进对TMZ治疗的代谢适应，并启动复发。我们有 确定了一种新的机制，其中RRM 2介导的dCTP和dGTP可以增强DNA修复反应 TMZ并促进对治疗的抵抗。基于此，我们假设RRM 2介导的RNR活性 对GBM的耐药性至关重要。为了研究这一假设，我们打算阐明RNR介导的 GBM中的化学抗性（目的1）。接下来，我们将评估一种血脑渗透性RRM 2抑制剂， GBM中RNR介导的化学抗性（目的2）。我们与Nanopharmaceutic建立了合作关系， 拥有生产临床级3-AP的专利，并将向我们提供临床级3-AP以测试其功效 进一步和推进我们对它可用于治疗GBM患者的作用机制的理解。 最后，我们打算研究由细菌产生的特异性核苷酸产生的治疗抗性的机制。 RRM 2介导的从头途径（Aim 3）。总的来说，我们的研究将提供新的见解， dNTP合成的变化与化疗期间GBM适应和耐药性相关。这 反过来，这些信息有望揭示延迟（如果不能预防）肿瘤复发的新方法。