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

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