Drivers of Metabolic Plasticity Promote Radiation Resistance in Glioblastoma Multiforme

项目摘要 多形性胶质母细胞瘤（GBM）是最难治疗的肿瘤之一，5年生存率低 率<10%。对放射治疗的内在和获得性抵抗显著地导致了难治性肿瘤。 这些肿瘤的性质。电离辐射（IR）主要通过产生游离的 自由基，特别是活性氧（ROS）。因此，调节氧化还原对于减轻 IR的致死作用，并增加RT的有效性。在这个建议中，我们假设GBM肿瘤， 可以通过重新连接它们的新陈代谢来产生对RT的抗氧化反应，这是一个主要的机制， 导致他们的生存和治疗失败。到目前为止，对GBM的代谢反应知之甚少 进行RT和代谢可塑性的分子驱动因素是未知的。在家长奖中，我们 为GBM中辐射诱导的代谢重编程提供证据，其中包括增强的 照射GBM细胞消耗葡萄糖和谷氨酰胺以及糖酵解流的转向 在抗氧化剂中，NADPH-磷酸戊糖途径（PPP）的中间体。基于 初步研究，我们假设IR诱导的GBM代谢重编程是精心策划的， 部分通过转录因子NRF 2的激活，这开启了代谢产物的转录。 驱动PPP的酶。我们还假设糖酵解中间体转移到PPP是 通过IR诱导的对氧化还原敏感的糖酵解酶PKM 2的抑制进一步放大。 在这里，我们建议扩展我们目前的工作模型的基础上，新的令人信服的数据，指向丝氨酸 合成途径（SSP）作为一个额外的辐射诱导的代谢途径，也有助于 GBM的代谢重组辐射增强的SSP活动是由NRF 2驱动的，与NRF 2保持一致 是GBM中IR诱导的代谢重编程的协调者。然而，我们也发现， IR激活HIF-1通路独立于缺氧和IR诱导的SSP酶上调 HIF-1a抑制完全阻止表达，表明这两种氧化还原- 协调RT后GBM代谢重新布线的敏感因子， 通过PPP和从头SSP的途径和IR抗性，在PKM 2阻断的帮助下。 这些研究与来自家长奖的数据一起，将全面了解 GBM中辐射诱导的代谢重新连接，将阐明针对以下目标的干预策略： 改善这种可怕疾病的RT结果。

Project Summary Glioblastoma multiforme (GBM) is one of the most therapy-resistant tumors, with a dismal 5-year survival rate of <10%. Intrinsic and acquired resistance to radiation therapy contributes significantly to the refractory nature of these tumors. Ionizing radiation (IR) exerts its cytotoxic effects primarily by generating free radicals, in particular reactive oxygen species (ROS). Moderating redox is therefore critical to mitigating the lethal effects of IR and increase the effectiveness of RT. In this proposal we postulate that GBM tumors can generate an antioxidant response to RT by rewiring their metabolism and this is a major mechanism leading to their survival and treatment failure. As yet, little is known about the metabolic response of GBM undergoing RT and the molecular drivers of metabolic plasticity are unknown. In the parent award we provide evidence for radiation-induced metabolic reprogramming in GBM, which includes enhanced consumption of glucose and glutamine by irradiated GBM cells and diversion of the flow of glycolytic intermediates into the antioxidant, NADPH-producing pentose phosphate pathway (PPP). Based on preliminary studies, we hypothesize that the IR-induced metabolic reprogramming in GBM is orchestrated in part by the activation of the transcription factor NRF2, which turns on the transcription of metabolic enzymes that drive the PPP. We also hypothesize that diversion of glycolytic intermediates into the PPP is further amplified by the IR-induced inhibition of the redox-sensitive, glycolytic enzyme PKM2. Here, we propose to expand our current working model based on new compelling data that point to serine synthesis pathway (SSP) as an additional radiation-induced metabolic pathway that also contributes to metabolic rewiring in GBM. The radiation-enhanced SSP activity is driven by NRF2, in keeping with NRF2 being the orchestrator of IR-induced metabolic reprogramming in GBM. However, we have also shown that IR activates the HIF-1 pathway independently of hypoxia and IR-induced upregulation of SSP enzyme expression is completely prevented by HIF-1a inhibition, suggesting dual roles for these two redox- sensitive factors in coordinating the metabolic rewiring of GBM following RT that drives antioxidant pathways and IR resistance through the PPP and de novo SSP, with assistance from PKM2 blockade. Together with the body of data from the parent award, these studies will build a comprehensive picture of radiation-induced metabolic rewiring in GBM that will illuminate interventional strategies aimed at improving RT outcomes in this dreadful disease.