Optimizing radiation therapy through the manipulation of glutamine metabolism

项目摘要 高达50%的局部晚期宫颈癌患者接受了目前的标准治疗， 护理将使这种治疗失败，并且目前没有治愈复发或转移性疾病的方法。作为 我们最近完成的一项研究的结果是， 和辐射抗性，我们发现宫颈癌高度依赖于谷氨酰胺。 最近的数据还表明，靶向谷氨酰胺代谢不仅限制了肿瘤细胞的生长， 生长，而且还通过重编程肿瘤中的巨噬细胞来提高抗肿瘤免疫力 微环境（TME）向更促炎表型转变。考虑到辐射 也已经显示RT疗法（RT）促进抗肿瘤免疫，这些发现表明， 靶向谷氨酰胺代谢和RT的组合可以协同增强抗肿瘤作用， 免疫力和实现长期肿瘤控制。此续期R 01申请的目的是 进行临床前机制研究和相应的药物启动的临床试验， 支持用放射疗法靶向谷氨酰胺代谢作为新的治疗策略， 抗辐射宫颈癌。我们的假设是谷氨酰胺的抑制 代谢通过对肿瘤细胞的协同代谢效应增强辐射敏感性 和免疫细胞。在具体目标1中，我们将测试 转氨酶抑制剂，CB-839，和放化疗改善抗肿瘤免疫反应， 在研究者启动的I/II期研究背景下采集的成对人类肿瘤标本 临床试验在具体目标2中，使用2D和3D共培养系统，我们将确定是否 谷氨酰胺代谢抑制的细胞毒性作用主要通过 对肿瘤细胞的代谢作用与对肿瘤细胞和巨噬细胞的组合作用。在 特异性目的3，使用患者来源的异种移植物（PDX）文库和新的遗传修饰， 工程小鼠模型（GEMM），我们将确定是否辐射修饰特性 CB-839依赖于肿瘤微环境的代谢编辑， 支持未来临床试验的治疗组合。这项工作将产生一个机械的 抑制谷氨酰胺代谢和RT的基本原理和测试预测生物标志物，以及 完成CB-839 +宫颈癌放化疗的首次人体试验。这 临床试验的独特之处在于它包括一种研究性新药CB-839， 常规分次外射束RT以及高剂量率低分次 近距离放射治疗该设计将提供关于RT剂量效应的有价值的人体数据 以及对放化疗和CB-839相关的TME变化的分级。

PROJECT SUMMARY Up to 50% of patients with locally advanced cervical cancer treated with the current standard of care will fail this treatment, and there is currently no cure for recurrent or metastatic disease. As a result of our recently completed studies of the connection between cervical cancer metabolism and radiation resistance, we have found that cervical cancer is highly dependent upon glutamine. Recent data has also demonstrated that targeting glutamine metabolism not only limits tumor cell growth, but also improves anti-tumor immunity by reprogramming macrophages in the tumor microenvironment (TME) towards a more pro-inflammatory phenotype. Given that radiation therapy (RT) has also been shown to promote anti-tumor immunity, these findings suggest that the combination of targeting glutamine metabolism and RT may synergize to enhance anti-tumor immunity and achieve long term tumor control. The purpose of this renewal R01 application is to perform preclinical mechanistic studies and a corresponding investigator-initiated clinical trial to support targeting glutamine metabolism with radiation therapy as a novel therapeutic strategy for radiation-resistant cervical cancers. Our working hypothesis is that inhibition of glutamine metabolism enhances radiation sensitivity through synergistic metabolic effects on tumor cells and immune cells within the TME. In Specific Aim 1, we will test whether the combination of the glutaminase inhibitor, CB-839, and chemoradiation improves anti-tumor immune responses using paired human tumor specimens collected in the context of an investigator initiated Phase I/II clinical trial. In Specific Aim 2, using 2D and 3D co-culture systems, we will determine whether the cytotoxic effects of inhibition of glutamine metabolism are mediated primarily through metabolic effects on tumor cells versus the combined effects on tumor cells and macrophages. In Specific Aim 3, using a patient derived xenograft (PDX) library and a novel genetically engineered mouse model (GEMM), we will determine whether the radiation modifying properties of CB-839 are dependent upon metabolic editing of the tumor microenvironment, and test new therapy combinations that will support future clinical trials. This work will generate a mechanistic rationale and test predictive biomarkers for the inhibition of glutamine metabolism and RT, and in so doing complete the first-in-human trial of CB-839 + chemoradiation in cervical cancer. This clinical trial is unique in that it includes an investigational new drug, CB-839, administered with both conventionally fractionated external beam RT as well as high dose rate hypofractionated brachytherapy. This design will provide valuable data in humans regarding the effects of RT dose and fractionation on chemoradiation and CB-839 associated changes in the TME.