Exploiting cell fate transition to overcome radiation resistance in glioblastoma

利用细胞命运转变克服胶质母细胞瘤的辐射抗性

• 批准号: 10719050
• 负责人: KRISHNA PL BHAT
• 金额: $ 70.96万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-28 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719050
• 关键词: Acid Phosphatase; Address; Adult; Affect; American; Bar Codes; Binding; Brain; Brain Neoplasms; CRISPR screen; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Clinical Trials; DNA Damage; DNA Repair Pathway; Data; Data Set; Dose; Effectiveness; Epigenetic Process; Evaluation; Excision; Exhibits; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genomics; Glioblastoma; Glioma; Goals; Grant; HMGB2 gene; In Vitro; Ionizing radiation; Knowledge; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mesenchymal; Mesenchymal Differentiation; Metabolic; Modeling; Molecular Target; Mus; Neuronal Differentiation; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Phase I Clinical Trials; Phenotype; Phosphoric Monoester Hydrolases; Photons; Post-Translational Protein Processing; Pre-Clinical Model; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Recurrence; Recurrent tumor; Resistance; Role; Signal Pathway; Site; Testing; The Cancer Genome Atlas; Toxic effect; Transcription Coactivator; Translating; Transplantation; United States; Verteporfin; Work; Xenograft Model; cell killing; chemoradiation; chemotherapy; clinically relevant; comparative efficacy; design; druggable target; effective therapy; experimental study; improved; in vivo; in vivo Model; inhibitor; molecular subtypes; neoplastic cell; neural; novel; phosphatase inhibitor; potential biomarker; pre-clinical; preclinical study; programs; protein complex; radiation resistance; radioresistant; response biomarker; stem cells; stem-like cell; transcription factor; transcriptional reprogramming; tumor; tumor behavior; tumor growth; whole genome

PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor that affects about 15,000 Americans every year. Despite maximal surgical resection and chemoradiation, GBMs remain incurable. GBMs are notoriously radiation resistant. Molecular subtyping of GBMs by genomic analyses of patient tumors identified three major subtypes, termed Proneural (PN), Classical or Mesenchymal (MES), based on gene expression patterns. Collaborative efforts between the Sulman and Bhat laboratories over the years has uncovered glioma stem-like cells (GSCs) closely resembling molecular subtypes of GBM. These states, however, exhibit plasticity and we pioneered the notion of PN to MES transition based on studies using patient derived GSCs linking MES signatures with radio- resistance and identifying master transcription factors associated with the MES subtype. New exciting preliminary data from our laboratories have identified three independent molecular targets associated with radiation resistance. Using whole-genome CRISPR screens to identify gene targets associated with enhanced radiation sensitivity as well as and mass spectrometric evaluation of radiation induced protein complexes, we have uncovered three players involved in metabolic, epigenetic and DNA repair pathways that can be targeted to overcome radiation resistance in GSCs. The overall goal of this proposal is to combine these druggable targets with the standard use of fractionated photon radiation therapy (RT) and convert GSCs from radioresistant to radiosensitive. In Aim 1, we will examine if inhibition of N-acylneuraminate-9-phosphatase (NANP) will lead to radiosensitization of GBM transitioning from MES to PN states via metabolic reprogramming. In Aim 2, we will test if targeting High Mobility Group Box-2 (HMGB2) leads to a block of MES transitioning and alterations of chromatin and if it is lethal in combination with radiation. Finally, in Aim 3, we will examine the radiosensitizing effects of neuronal differentiation with combined TAZ inhibitors and ionizing radiation in pre-clinical models of GBM. Our proposal is significant because this is the first comprehensive study to examine the radiosensitizing effects of cell state transition blockade in GBM. Data generated from this grant will encompass TCGA datasets, patient derived GSCs, clinically relevant xenograft models as well as testing of inhibitors in these models with a trajectory toward Phase I clinical trials to overcome radioresistance in patients with GBM.

项目总结