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.

项目概要 胶质母细胞瘤 (GBM) 是一种毁灭性的脑肿瘤，每年影响约 15,000 名美国人。尽管 通过最大程度的手术切除和放化疗，GBM 仍然无法治愈。 GBM 的辐射是出了名的 抵抗的。通过对患者肿瘤进行基因组分析对 GBM 进行分子亚型鉴定，确定了三种主要亚型， 根据基因表达模式，称为原神经 (PN)、经典或间充质 (MES)。协作性 Sulman 和 Bhat 实验室多年来的努力发现了神经胶质瘤干样细胞 (GSC) 与 GBM 的分子亚型非常相似。然而，这些状态表现出可塑性，我们开创了 PN 到 MES 过渡的概念基于使用患者衍生的 GSC 将 MES 特征与无线电连接起来的研究 抗性并识别与 MES 亚型相关的主转录因子。新的令人兴奋 我们实验室的初步数据已确定了与以下因素相关的三个独立的分子靶标： 抗辐射性。使用全基因组 CRISPR 筛选来识别与增强相关的基因靶标 辐射敏感性以及辐射诱导蛋白复合物的质谱评估，我们 发现了参与代谢、表观遗传和 DNA 修复途径的三个可靶向的参与者 克服 GSC 的辐射阻力。该提案的总体目标是将这些可药物靶点结合起来 标准使用分段光子放射治疗 (RT)，将 GSC 从耐辐射转变为耐辐射 辐射敏感。在目标 1 中，我们将检查 N-酰基神经氨酸-9-磷酸酶 (NANP) 的抑制是否会导致 GBM 的放射增敏作用通过代谢重编程从 MES 状态转变为 PN 状态。在目标 2 中，我们将 测试针对 High Mobility Group Box-2 (HMGB2) 是否会导致 MES 转换和更改受阻 染色质以及与辐射结合是否致命。最后，在目标 3 中，我们将检查放射增敏 联合 TAZ 抑制剂和电离辐射对临床前模型中神经元分化的影响 GBM。我们的建议很重要，因为这是第一个检查放射增敏的综合研究 GBM 中细胞状态转换阻断的影响。本次资助生成的数据将包含 TCGA 数据集， 患者来源的 GSC、临床相关的异种移植模型以及在这些模型中使用抑制剂进行的测试 克服 GBM 患者放射抗性的 I 期临床试验的轨迹。