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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要高达 50% 的局部晚期宫颈癌患者接受现行标准的治疗护理会使这种治疗失败，并且目前还没有治愈复发或转移性疾病的方法。作为我们最近完成的关于宫颈癌代谢之间关系的研究结果和抗辐射能力，我们发现宫颈癌高度依赖于谷氨酰胺。最近的数据还表明，针对谷氨酰胺代谢不仅限制肿瘤细胞生长，而且还通过重新编程肿瘤中的巨噬细胞来提高抗肿瘤免疫力微环境（TME）朝着更促炎的表型发展。鉴于辐射疗法（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放疗的结合可能协同增强抗肿瘤作用免疫并实现肿瘤的长期控制。此更新 R01 申请的目的是进行临床前机制研究和相应的研究者发起的临床试验支持以放射治疗为目标的谷氨酰胺代谢作为一种新的治疗策略抗辐射宫颈癌。我们的工作假设是谷氨酰胺的抑制代谢通过对肿瘤细胞的协同代谢作用增强辐射敏感性以及 TME 内的免疫细胞。在具体目标 1 中，我们将测试以下组合是否有效：谷氨酰胺酶抑制剂、CB-839 和放化疗可改善抗肿瘤免疫反应在研究者发起的 I/II 期研究中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，我们将确定是否抑制谷氨酰胺代谢的细胞毒性作用主要是通过对肿瘤细胞的代谢影响与对肿瘤细胞和巨噬细胞的综合影响。在具体目标 3，使用患者来源的异种移植物 (PDX) 文库和新型基因工程小鼠模型（GEMM），我们将确定辐射修饰特性是否 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。这项工作将产生一个机制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，以及这样就完成了 CB-839 + 放化疗治疗宫颈癌的首次人体试验。这临床试验的独特之处在于它包括一种研究性新药 CB-839，传统分割外照射放疗以及高剂量率大分割近距离放射治疗。该设计将为人类提供有关 RT 剂量影响的宝贵数据以及放化疗和 CB-839 相关 TME 变化的分级。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Serum squamous cell carcinoma antigen as an early indicator of response during therapy of cervical cancer.

DOI：
10.1038/bjc.2017.390
发表时间：
2018-01
期刊：
British journal of cancer
影响因子：
8.8
作者：
Markovina S;Wang S;Henke LE;Luke CJ;Pak SC;DeWees T;Pfeifer JD;Schwarz JK;Liu W;Chen S;Mutch D;Wang X;Powell MA;Siegel BA;Dehdashti F;Silverman GA;Grigsby PW
通讯作者：
Grigsby PW

Clinical outcomes and differential effects of PI3K pathway mutation in obese versus non-obese patients with cervical cancer.

DOI：
10.18632/oncotarget.23664
发表时间：
2018-01-09
期刊：
Oncotarget
影响因子：
0
作者：
Grigsby P;Elhammali A;Ruiz F;Markovina S;McLellan MD;Miller CA;Chundury A;Ta NL;Rashmi R;Pfeifer JD;Fulton RS;DeWees T;Schwarz JK
通讯作者：
Schwarz JK

HPV-EM: an accurate HPV detection and genotyping EM algorithm