Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme

摘要 放射治疗是改善局部控制的一种非常有效的治疗方式。 以及许多癌症类型的总存活率。然而，多形性胶质母细胞瘤(GBM) 表现出显著的抗辐射性能。尽管如此，术后放疗(总剂量60Gyin 2GY部分)是唯一可以提高GBM总存活率的治疗方式 患者中，GBM普遍复发，并具有致命性。因此，对RT的抵抗是一个主要的原因 导致治疗失败的因素。克服这些肿瘤的辐射抵抗力是其中之一 放射肿瘤学剩余的主要前沿领域，如果得到解决，可能 极大地改善这种疾病的预后。在众多促成因素中 已经提出，GBM代谢及其在产生抗病中的作用 氧化应激，如在RT期间，是一个有希望的治疗角度，我们将利用 在这份提案中。具体地说，我们有证据表明，受辐射的GBM细胞重新编程了它们的 代谢向抗氧化途径，通过漏斗葡萄糖通过NADPH- 产生磷酸戊糖途径(PPP)。这样的代谢重新编程在 RT部分由糖酵解酶PKM2介导，部分由转录介导 因子NRF2。依赖氧化应激的PKM2失活或NRF2激活， 两者都会导致糖酵解中间产物重新进入PPP。此外，我们还有 PKM2是NRF2目标的证据。因此，我们假设PKM2和NRF2 在辐射的GBM细胞中协同驱动抗氧化剂代谢反应 促进对RT的抵抗。重要的是，PKM2在 而正常脑组织仅表达PKM1。还有，小分子 PKM2的激活剂可加剧氧化应激并具有抗肿瘤作用 活性，尽管它们尚未在GBM或RT中进行测试。这些激活剂交叉 血脑屏障使其适合与RT联合致敏GBM 肿瘤。因此，也有人提出，干扰NRF2-PKM2-代谢 Axis会限制抗氧化剂，促进生存的代谢重新编程 辐射并改善RT对人和小鼠GBM模型的影响。

ABSTRACT Radiation therapy (RT) is a very effective treatment modality for improving local control and overall survival for many cancer types. However, glioblastoma multiforme (GBM) displays remarkable radioresistance. Although, post-surgical RT (total dose of 60Gy in 2Gy fractions) is the only treatment modality that increases overall survival for GBM patients, GBM universally recurs and is fatal. Resistance to RT is therefore a major contributor to treatment failure. Overcoming radiation resistance of these tumors is one of the major remaining frontiers in Radiation Oncology that, if resolved, could dramatically improve outcomes in this disease. Amongst the many contributing factors that have been proposed, GBM metabolism and its role in generating resistance to oxidative stress, such as during RT is a promising therapeutic angle that we will exploit in this proposal. Specifically, we have evidence that irradiated GBM cells reprogram their metabolism towards antioxidant pathways, by funneling glucose through the NADPH- generating pentose phosphate pathway (PPP). Such metabolic reprogramming during RT is mediated in part by the glycolytic enzyme PKM2 and in part by the transcription factor NRF2. Oxidative stress-dependent inactivation of PKM2 or activation of NRF2, both result in rerouting of glycolytic intermediates into the PPP. In addition, we have evidence that PKM2 is a NRF2 target. Therefore, we hypothesize that PKM2 and NRF2 cooperate in driving an antioxidant metabolic response in irradiated GBM cells that promotes resistance to RT. Of importance is the fact that PKM2 is overexpressed in GBM tumors, while normal brain tissue only expresses PKM1. Also, small molecule activators of PKM2 are available that exacerbate oxidative stress and have anti-tumor activity, although they have not been tested in GBM or with RT. These activators cross the blood brain barrier making them suitable for combining with RT to sensitize GBM tumors. Therefore, it is also proposed that interfering with the NRF2-PKM2-metabolism axis would limit the antioxidant, pro-survival metabolic reprogramming induced by radiation and improve the effect of RT in human and mouse models of GBM.