Cellular Plasticity and equilibrium in GBM Progression

GBM 进展中的细胞可塑性和平衡

• 批准号: 10666657
• 负责人: Atique U. Ahmed
• 金额: $ 44.93万
• 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/10666657
• 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 Maintenance; 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; Learning; 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; Radiation therapy; Recurrence; Recurrent tumor; Regulation; Research; Resistance; Ribonucleotide Reductase; Ribonucleotide Reductase Subunit; Safety; Sampling; Stress; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; Triapine; 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.

项目总结 为了提高我们对胶质母细胞瘤(GBM)治疗耐药的认识，有必要对 治疗过程中的单个细胞助长了基底膜肿瘤的复发。然而，研究这些问题是具有挑战性的。 常规放疗和化疗期间的GBM，因为在此期间患者样本的可获得性有限 时间段。我们的实验室在患者来源的异种移植模型中进行了单细胞RNA测序筛选 替莫唑胺(TMZ)治疗期间的基底膜。我们的分析显示，核糖核苷酸还原酶调控 亚基2(RRM2)介导正常DNA所必需的脱氧核苷三磷酸(DNTPs)的产生 复制可稳定细胞生长，促进对TMZ治疗的代谢适应，并启动复发。我们有 发现了RRM2介导的dCTP和dGTP促进DNA修复的新机制 TMZ并促进对治疗的抵抗。在此基础上，我们假设RRM2介导的RNR活性 是GBM化疗耐药的关键因素。为了研究这一假说，我们打算阐明RNR介导的 肾小球系膜细胞的化疗耐药(目标1)。接下来，我们将评估一种血脑渗透性RRM2抑制剂，以防止 RnR介导的GBM化疗耐药(AIM 2)。我们与纳米制药公司建立了合作关系，该公司 拥有生产临床级3-AP的专利，并将为我们提供临床级3-AP以测试其疗效 进一步促进我们对其用于治疗GBM患者的作用机制的理解。 最后，我们打算研究产生治疗耐药的特定核苷酸的机制。 RRM2介导的从头通路(Aim 3)。总而言之，我们的研究将提供关于以下方面的新见解 化疗期间与GBM适应和耐药相关的dNTP合成的变化。这 反过来，信息有望揭示延缓(如果不是防止)肿瘤复发的新方法。

项目成果

Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells.

• DOI: 10.3390/cancers12113126
• 发表时间: 2020-10-26
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Caragher S;Miska J;Shireman J;Park CH;Muroski M;Lesniak MS;Ahmed AU
• 通讯作者: Ahmed AU

Radiotherapy and Glioma Stem Cells: Searching for Chinks in Cellular Armor.

放射疗法和神经胶质瘤干细胞：在细胞装甲中寻找切换。

• DOI: 10.1007/s40778-017-0102-8
• 发表时间: 2017-12
• 期刊: Current stem cell reports
• 影响因子: 1.4
• 作者: Caragher SP;Sachdev S;Ahmed A
• 通讯作者: Ahmed A

LNX1 Modulates Notch1 Signaling to Promote Expansion of the Glioma Stem Cell Population during Temozolomide Therapy in Glioblastoma.

• DOI: 10.3390/cancers12123505
• 发表时间: 2020-11-25
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Baisiwala S;Hall RR 3rd;Saathoff MR;M Shireman J;Park C;Budhiraja S;Goel C;Warnke L;Hardiman C;Wang JY;McCortney K;Horbinski CM;Ahmed AU
• 通讯作者: Ahmed AU

Spelling Out CICs: A Multi-Organ Examination of the Contributions of Cancer Initiating Cells' Role in Tumor Progression.

拼写CICS：对癌症在肿瘤进展中发挥作用的贡献的多器官检查。

• DOI: 10.1007/s12015-021-10195-x
• 发表时间: 2022-01
• 期刊: STEM CELL REVIEWS AND REPORTS
• 影响因子: 4.8
• 作者: Baisiwala, Shivani;Budhiraja, Shreya;Goel, Chirag;Nandoliya, Khizar R.;Saathoff, Miranda R.;Ahmed, Atique U.
• 通讯作者: Ahmed, Atique U.

BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine.

• DOI: 10.1126/scitranslmed.aax2879
• 发表时间: 2020-08-26
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Kanojia D;Panek WK;Cordero A;Fares J;Xiao A;Savchuk S;Kumar K;Xiao T;Pituch KC;Miska J;Zhang P;Kam KL;Horbinski C;Balyasnikova IV;Ahmed AU;Lesniak MS
• 通讯作者: Lesniak MS