Targeting Nucleotide Metabolism to Overcome Therapy Resistance in Glioblastoma

摘要 胶质母细胞瘤(GBM)是最常见的侵袭性原发脑肿瘤， 一致致命，中位生存期约为1.5年。像手术和化疗一样， 放射治疗(RT)是几乎所有GBM患者的关键治疗方法，并反复 在多个随机试验中改善了患者的存活率。尽管如此，80%的GBM重复出现在高水平 剂量RT野。因此，迫切需要制定战略，以克服GBM RT- 抵抗进一步改善患者预后。GBM细胞表现出深刻的癌症特异性 代谢异常，包括嘌呤合成增加，以促进增殖、侵袭和 生死存亡。我们发现，嘌呤合成增加的代谢表型也 通过促进RT诱导的DNA损伤的修复，介导GBM对RT的抗性。这 霉酚酸酯可在临床前模型中克服嘌呤介导的RT耐药 (MMF)，一种FDA批准的中枢神经系统嘌呤合成穿透性抑制剂。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基底膜是否源于 MMF治疗的最大好处。最后，我们将进行临床试验，以确定 GBM与RT联合应用MMF的最大耐受量 确认此剂量在GBM组织中达到有效浓度。总而言之，这些研究将 (1)确定在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损伤诱导的合理结合 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)确定联合RT和MMF是否应该 在对GBM患者的随机试验中进行评估。

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.