Optimizing radiation therapy through the manipulation of glutamine metabolism

通过操纵谷氨酰胺代谢优化放射治疗

• 批准号: 10705856
• 负责人: Julie Kristina Schwarz
• 金额: $ 36.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705856
• 关键词: 18F-Glutamine; 3-Dimensional; Animals; Biological Availability; Biological Markers; Biopsy; Blood; Brachytherapy; Cancer Therapy Evaluation Program; Carbon; Cell Culture System; Cells; Cervix Neoplasms; Cisplatin; Clinical Trials; Coculture Techniques; Data; Diagnosis; Disease; Dose; Dose Rate; Equilibrium; External Beam Radiation Therapy; Flow Cytometry; Fractionation; Future; Genetically Engineered Mouse; Glutaminase; Glutamine; Glutathione Metabolism Pathway; Human; Human Papillomavirus; Hypoxia; Immune; Immunocompetent; In Vitro; Inflammatory; Investigational Drugs; Label; Lead; Libraries; Macrophage; Malignant neoplasm of cervix uteri; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Modeling; Monitor; Mus; Mutation; Nucleotides; Nutrient; Oral; Output; Oxidation-Reduction; Oxidative Stress; PIK3CA gene; PIK3CG gene; Pathway interactions; Patients; Phase I/II Clinical Trial; Phenotype; Physiological; Positron-Emission Tomography; Property; Publishing; Pyruvate; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Recurrence; Research; Research Personnel; Resistance; Safety; Source; Specimen; Stimulus; Sulfhydryl Compounds; System; Testing; Time; Treatment Efficacy; Tumor Immunity; Work; Xenograft Model; amino acid metabolism; anti-tumor immune response; cell growth; chemoradiation; clinical translation; clinically relevant; cytotoxic; design; experimental study; first-in-human; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; image guided; improved; in vivo; inhibitor; metabolic imaging; metabolomics; mutant; neoplastic cell; new combination therapies; novel; novel therapeutic intervention; patient derived xenograft model; pre-clinical; preclinical study; predicting response; predictive marker; radiation effect; radiation resistance; radioresistant; response; standard of care; synergism; targeted exome sequencing; three dimensional cell culture; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor metabolism; tumor microenvironment; two-dimensional; uptake; 18F-Glutamine; 3-Dimensional; Animals; Biological Availability; Biological Markers; Biopsy; Blood; Brachytherapy; Cancer Therapy Evaluation Program; Carbon; Cell Culture System; Cells; Cervix Neoplasms; Cisplatin; Clinical Trials; Coculture Techniques; Data; Diagnosis; Disease; Dose; Dose Rate; Equilibrium; External Beam Radiation Therapy; Flow Cytometry; Fractionation; Future; Genetically Engineered Mouse; Glutaminase; Glutamine; Glutathione Metabolism Pathway; Human; Human Papillomavirus; Hypoxia; Immune; Immunocompetent; In Vitro; Inflammatory; Investigational Drugs; Label; Lead; Libraries; Macrophage; Malignant neoplasm of cervix uteri; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Modeling; Monitor; Mus; Mutation; Nucleotides; Nutrient; Oral; Output; Oxidation-Reduction; Oxidative Stress; PIK3CA gene; PIK3CG gene; Pathway interactions; Patients; Phase I/II Clinical Trial; Phenotype; Physiological; Positron-Emission Tomography; Property; Publishing; Pyruvate; Radiation; Radiation Tolerance; Radiation therapy; Radiosensitization; Recurrence; Research; Research Personnel; Resistance; Safety; Source; Specimen; Stimulus; Sulfhydryl Compounds; System; Testing; Time; Treatment Efficacy; Tumor Immunity; Work; Xenograft Model; amino acid metabolism; anti-tumor immune response; cell growth; chemoradiation; clinical translation; clinically relevant; cytotoxic; design; experimental study; first-in-human; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; image guided; improved; in vivo; inhibitor; metabolic imaging; metabolomics; mutant; neoplastic cell; new combination therapies; novel; novel therapeutic intervention; patient derived xenograft model; pre-clinical; preclinical study; predicting response; predictive marker; radiation effect; radiation resistance; radioresistant; response; standard of care; synergism; targeted exome sequencing; three dimensional cell culture; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor metabolism; tumor microenvironment; two-dimensional; uptake

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.

项目摘要 多达50％的局部晚期宫颈癌患者接受了当前标准的治疗 护理将使这种治疗失败，目前无法治愈复发或转移性疾病。作为 我们最近完成的宫颈癌代谢之间联系的研究结果 和辐射耐药性，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 生长，但也通过在肿瘤中重新编程巨噬细胞来改善抗肿瘤免疫力 微环境（TME）朝着更促炎的表型。鉴于该辐射 治疗（RT）也已显示可促进抗肿瘤免疫，这些发现表明 靶向谷氨酰胺代谢和RT的组合可能协同作用以增强抗肿瘤 免疫并实现长期肿瘤控制。此续签R01申请的目的是 进行临床前机械研究和相应的研究者引发的临床试验 支持靶向谷氨酰胺代谢，以放射疗法为一种新的治疗策略 抗辐射的宫颈癌。我们的工作假设是抑制谷氨酰胺 代谢通过对肿瘤细胞的协同代谢作用增强辐射敏感性 和TME内的免疫细胞。在特定目标1中，我们将测试是否合并 谷氨酰胺酶抑制剂，CB-839和化学放疗可改善抗肿瘤免疫反应 在研究者启动I/II的背景下收集的配对的人类肿瘤标本 临床试验。在特定的目标2中，使用2D和3D共培养系统，我们将确定是否确定是否是否 抑制谷氨酰胺代谢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综合作用。在 特定的目标3，使用衍生异种移植（PDX）库和新型遗传学的患者 工程鼠标模型（GEMM），我们将确定辐射修改属性是否 CB-839的依赖于肿瘤微环境的代谢编辑，并测试了新的 将支持未来临床试验的治疗组合。这项工作将产生机械 基本原理和测试预测性生物标志物抑制谷氨酰胺代谢和RT，以及 因此，完成CB-839 +宫颈癌化学放疗的第一项人类试验。这 临床试验是独一无二的，因为它包括一种调查新药CB-839 传统上分馏的外束RT和高剂量率降低了 近距离放射治疗。该设计将为人类提供有关RT剂量影响的宝贵数据 TME的化学放疗和CB-839相关变化的分馏。