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性脑肿瘤， 平均存活时间约为1.5年。像手术和化疗， 放射（RT）是几乎所有GBM患者的关键治疗， 在多项随机试验中提高了患者生存率。尽管如此，80%的GBM在高血糖范围内复发。 剂量RT场。因此，迫切需要制定克服GBM RT的策略。 进一步改善患者预后的阻力。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的抗性。这 在临床前模型中，霉酚酸酯可克服嘌呤介导的RT抗性 (MMF)，FDA批准的和CNS渗透嘌呤合成抑制剂。本研究 我们将确定RT反应和嘌呤合成如何相互调节， GBM。我们还将确定是否具有最大嘌呤合成活性的GBM衍生自 最大的受益是MMF治疗。最后，我们将进行临床试验，以确定 GBM患者接受MMF联合RT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损伤诱导剂的合理组合， （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 在GBM患者的随机试验中进行了评估。

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.