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.

项目摘要 胶质母细胞瘤（GBM）是一种毁灭性的脑瘤，每年影响约15,000名美国人。尽管 最大的手术切除和化学放疗，GBM仍然无法治愈。 GBM是众所周知的辐射 抵抗的。通过对患者肿瘤的基因组分析对GBM的分子亚型鉴定出三个主要亚型， 基于基因表达模式，被称为胸膜（PN），经典或间充质（MES）。协作 多年来，硫磺实验室和BHAT实验室之间的努力已经发现了神经胶质瘤干细胞（GSC） 与GBM的分子亚型非常相似。但是，这些状态表现出可塑性，我们开创了 基于研究使用患者衍生的GSC将MES特征与Roadio-Roadion-Radio-Radio-Radio-Roady- 抗性和识别与MES亚型相关的主转录因子。新令人兴奋 我们实验室的初步数据已经确定了与 辐射阻力。使用全基因组CRISPR屏幕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 发现了三名参与代谢，表观遗传和DNA修复途径的玩家 克服GSC中的辐射抗性。该提案的总体目标是结合这些可毒品目标 通过标准使用分离光子放射疗法（RT），并将GSC从放射线抗性转换为 放射敏感。在AIM 1中，我们将检查抑制N-酰胺氨酸-9-磷酸酶（NANP）是否会导致 GBM通过代谢重编程从MES到PN状态的放射敏化。在AIM 2中，我们将 测试是否针对高移动性组Box-2（HMGB2）导致MES过渡和改变 染色质，如果它与辐射结合使用。最后，在AIM 3中，我们将检查放射敏感性 神经元分化与TAZ抑制剂组合的影响和电离辐射在临床前模型中的电离辐射的影响 GBM。我们的建议很重要，因为这是检查放射敏化的首次全面研究 细胞状态过渡阻滞在GBM中的影响。从该赠款生成的数据将包含TCGA数据集， 患者衍生的GSC，临床相关的异种移植模型以及对这些模型中抑制剂的测试 对I期临床试验进行的轨迹，以克服GBM患者的放射线疗程。