Targeting Nucleotide Metabolism to Overcome Therapy Resistance in Glioblastoma

靶向核苷酸代谢克服胶质母细胞瘤的治疗耐药性

基本信息

批准号：
10361529
负责人：
Daniel R Wahl
金额：
$ 56.13万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361529
关键词：
Acute Affect Biological Assay Brain Neoplasms Cells Chemotherapy and/or radiation Clinical Clinical Trials Combined Modality Therapy Communication DNA Damage DNA Repair DNA-dependent protein kinase Data Development Dose Excision Exhibits FDA approved FRAP1 gene Glioblastoma Goals Guanosine Triphosphate Individual Interruption Link Malignant Neoplasms Mass Spectrum Analysis Maximum Tolerated Dose Measures Mediating Mediator of activation protein Metabolic Methodology Modeling Molecular Mus Nature Neurosphere Nonhomologous DNA End Joining Nucleotides Operative Surgical Procedures Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Pre-Clinical Model Primary Brain Neoplasms Proto-Oncogene Proteins c-akt Purine Antagonist Purines Pyrimidines Radiation Radiation Dose Unit Radiation Induced DNA Damage Recurrence Regulation Reporter Research Research Proposals Resistance Safety Signal Transduction Signaling Molecule Supplementation Testing Therapeutic Tissues Tracer Tumor Tissue Work ds-DNA efficacy evaluation experimental study genetic approach guanylate improved in vitro Model in vivo inhibitor metabolic phenotype metabolomics mycophenolate mofetil neurosarcoidosis nucleotide analog nucleotide metabolism patient derived xenograft model phosphoproteomics predicting response purine metabolism rac1 GTP-Binding Protein radiation effect radiation resistance radiation response radioresistant randomized trial repaired response stable isotope tumor

项目摘要

ABSTRACT Glioblastoma (GBM) is the most common aggressive primary brain tumor and is uniformly fatal with a median survival of around 1.5 years. Like surgery and chemotherapy, radiation (RT) is a critical treatment for nearly every patient with GBM and has repeatedly improved patient survival in multiple randomized trials. Still, 80% of GBMs recur within the high dose RT field. Thus, there is a critical need to develop strategies to overcome GBM RT- resistance to further improve patient outcomes. GBM cells exhibit profound cancer-specific metabolic abnormalities, including elevated purine synthesis, to fuel proliferation, invasion and survival. We have found that the metabolic phenotype of elevated purine synthesis also mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. This purine-mediated RT resistance can be overcome in preclinical models by mycophenolate mofetil (MMF), an FDA-approved and CNS-penetrant inhibitor of purine synthesis. In this research proposal we will determine how the RT response and purine synthesis regulate one another in GBM. We will also determine if the GBMs with the greatest activity of purine synthesis derive the greatest benefit from MMF treatment. Finally, we will perform a clinical trial to determine the maximum tolerated dose of MMF given in combination with RT for patients with GBM and confirm that this dose reaches active concentrations in GBM tissue. Together, these studies will (1) Determine mechanistic links between the RT response and purine metabolism in GBM that will facilitate the rational combination of metabolic inhibitors with DNA damage inducing therapeutics, (2) Determine whether measuring purine synthesis rates could predict GBM response to MMF treatment, and (3) Determine whether combined RT and MMF should be evaluated in randomized trials for patients with GBM.

抽象的胶质母细胞瘤 (GBM) 是最常见的侵袭性原发性脑肿瘤，均是致命的，中位生存期约为 1.5 年。就像手术和化疗一样，放射 (RT) 是几乎所有 GBM 患者的关键治疗方法，并且已多次在多项随机试验中提高了患者的生存率。尽管如此，80% 的 GBM 在高复发率范围内复发剂量 RT 场。因此，迫切需要制定克服 GBM RT-的策略抵抗力进一步改善患者的治疗效果。 GBM 细胞表现出深刻的癌症特异性代谢异常，包括嘌呤合成升高，以促进增殖、侵袭和生存。我们发现嘌呤合成升高的代谢表型也通过促进 RT 诱导的 DNA 损伤的修复来介导 GBM 对 RT 的抵抗。这吗替麦考酚酯可以在临床前模型中克服嘌呤介导的 RT 耐药性 (MMF)，一种 FDA 批准的中枢神经系统渗透性嘌呤合成抑制剂。在这项研究中我们将确定 RT 反应和嘌呤合成如何在 GBM。我们还将确定具有最大嘌呤合成活性的 GBM 是否源自 MMF 治疗的最大益处。最后，我们将进行临床试验以确定对于 GBM 患者和放疗联合给予 MMF 的最大耐受剂量确认该剂量在 GBM 组织中达到活性浓度。这些研究共同将 (1) 确定 GBM 中 RT 反应和嘌呤代谢之间的机制联系将促进代谢抑制剂与DNA损伤诱导的合理组合治疗学，(2) 确定测量嘌呤合成率是否可以预测 GBM 对 MMF 治疗的反应，以及 (3) 确定是否应联合 RT 和 MMF GBM 患者的随机试验中进行了评估。