Optimizing radiation therapy through the manipulation of glutamine metabolism

项目总结 高达50%的局部晚期宫颈癌患者接受当前标准的 这种治疗将失败，目前还没有治愈复发或转移性疾病的方法。AS 我们最近完成的关于宫颈癌代谢之间的联系的研究的结果 和辐射抗性，我们发现宫颈癌高度依赖谷氨酰胺。 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 生长，但也通过对肿瘤中的巨噬细胞重新编程来提高抗肿瘤免疫 微环境(TME)向更促炎的表型转变。考虑到这种辐射 治疗(RT)也被证明可以促进抗肿瘤免疫，这些发现表明 靶向谷氨酰胺代谢与RT联合应用可能协同增强抗肿瘤作用 免疫和实现肿瘤的长期控制。此续订R01申请的目的是 执行临床前机制研究和相应的研究人员发起的临床试验 支持以谷氨酰胺代谢为靶点的放射治疗作为一种新的治疗策略 耐辐射的宫颈癌。我们的工作假设是谷氨酰胺的抑制作用 代谢通过对肿瘤细胞的协同代谢作用增强放射敏感性 和TME内的免疫细胞。在具体目标1中，我们将测试 谷氨酰胺酶抑制剂CB-839和放化疗改善抗肿瘤免疫反应 在研究人员启动阶段I/II的背景下收集的配对人类肿瘤标本 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 谷氨酰胺代谢抑制的细胞毒作用主要通过 代谢对肿瘤细胞的影响与对肿瘤细胞和巨噬细胞的联合作用。在……里面 特定目标3，使用患者来源的异种移植(PDX)文库和一种新的基因 工程化小鼠模型(GEMM)，我们将确定是否具有辐射修饰特性 CB-839依赖于肿瘤微环境的代谢编辑，并测试新的 将支持未来临床试验的治疗组合。这项工作将产生一种机械性的 谷氨酰胺代谢和RT抑制的基本原理和试验预测生物标志物，以及在 这样做就完成了CB-839+化疗治疗宫颈癌的第一次人体试验。这 临床试验的独特之处在于，它包括一种正在研究的新药CB-839， 常规分割的外束RT以及高剂量率低分割 近距离放射治疗。这一设计将在人体中提供关于放射治疗剂量影响的有价值的数据 和分级对TME的化学辐射和CB-839相关的变化。

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.