Research Project Cervical Cancer

宫颈癌研究项目

基本信息

批准号：
10715022
负责人：
Julie Kristina Schwarz
金额：
$ 38.68万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10715022
关键词：
Address Antibodies Bioinformatics Biology Biopsy CD8-Positive T-Lymphocytes Cancer Etiology Cell Count Cell physiology Cells Cervix Neoplasms Chronic Cisplatin Classification Coculture Techniques Combined Modality Therapy Communication Data Data Analyses Deoxyglucose Dependence Development Exhibits Failure Gene Expression Genetic Transcription Genetically Engineered Mouse Glucose Glycolysis Goals Human Human Papillomavirus Image Immune Immunocompetent Infection Inflammation Inflammatory Macrophage Malignant neoplasm of cervix uteri Mediating Mesenchymal Metabolic Metabolic Pathway Metabolism Methods Modeling Mus Organoids Oxidation-Reduction Patients Pelvis Pharmaceutical Preparations Phenotype Positron-Emission Tomography Proteomics Radiation Radiation Oncology Radiation Tolerance Radiation therapy Radiation-Induced Change Reactive Oxygen Species Recurrent disease Recurrent tumor Relapse Research Project Grants Resistance SOD2 gene Sampling Signal Transduction T-Lymphocyte Testing Therapeutic Time Tissue Model Tracer Training Tumor Bank Tumor Cell Biology Tumor Immunity Tumor Promotion Tumor-associated macrophages Universities Up-Regulation Washington Work biological specimen archives cell type chemoradiation clinically relevant design experimental study functional genomics glucose uptake human data human model human papilloma virus oncogene imaging approach immune checkpoint blockade improved improved outcome inhibitor innovation metabolic phenotype metabolomics mitochondrial metabolism mouse model neoplastic cell novel permissiveness preclinical study predicting response programs prospective radiation effect radiation resistance single nucleus RNA-sequencing standard of care transcriptome sequencing tumor tumor growth tumor microenvironment uptake

项目摘要

PROJECT 1 SUMMARY (CERVIX) The standard of care (SOC) for locally advanced cervical cancer, pelvic radiation (RT) with concurrent cisplatin, is associated with a 30-50% failure rate, and there is no cure for recurrent disease. Most cervical cancers are caused by infection with Human Papilloma Virus (HPV), and persistent expression of HPV oncogenes supports a state of chronic stromal inflammation mediated by macrophages. Preclinical studies suggest that tumor associated macrophages (TAMs) are the most abundant cell type in the tumor microenvironment (TME) after RT and exhibit “M2-like” phenotypes that suppress the development of anti-tumor immunity. In our previous work, we demonstrated that cervical tumor 18F-Fluoro-deoxy-glucose (FDG) uptake on pretreatment positron emission tomography (PET) is associated with increased TAMs with “M2-like” phenotypes in the cervix TME, and that co- culture of cervix tumor cells with TAMs increases tumor cell glucose uptake. We propose that TAMs and tumor cells in the TME co-evolve and mutually adapt their glucose and ROS metabolism to optimize tumor growth. In this proposal, we will test the hypothesis that SOC CRT induces ROS-mediated “metabolic switches” that alter gene transcription and metabolism in each cell type, providing a therapeutic opportunity to limit this metabolic co-dependency and improve outcomes after SOC CRT by promoting RT induced anti-tumor immunity. Here we will use a combination of state of the art single cell and spatially resolved profiling of human tumors together with state of the are imaging to determine the impact of SOC CRT induced changes in metabolism in tumor cells and TAMs on CRT sensitivity, and perform mechanistic preclinical studies to determine how this impacts the development of anti-tumor immunity. In Aim 1 we will determine the longitudinal impact of SOC CRT on metabolism and inflammatory signaling in cervix tumor cells. Our preliminary data supports targeting CRT induced upregulation of SOD2 and NRF2 in tumor cells. We will study CRT associated changes in ROS and mitochondrial metabolism using tumor organoids and novel mouse models. In Aim 2 we will determine the impact of SOC CRT on TAM and T cell phenotype and function in the cervix TME. We will study the effect of TAM targeting using novel imaging approaches, antibody depletion and CCR2 inhibitors in mouse models. In Aim 3 we will integrate longitudinal changes in PET imaging features with CRT associated changes in gene expression to improve patient classifiers and response prediction. In these studies, we will use FDG in addition to 64Cu- DOTA-ECLi, a novel PET tracer for CCR2+ TAMs. Finally, we will work with a trainee from our Training Core, METEORITE, to prioritize new leads from our human data. This trainee will explore the contribution of immune checkpoint blockade (ICB) when added to SOC CRT. ICB is well known to alter metabolism in immune cells, and we will synthesize our data and approaches to achieve our ultimate goal which is to incorporate immunometabolism into novel radiosentization strategies. These experiments will optimize a new treatment combination reprogramming TAM metabolism as a novel means to improve outcomes after SOC CRT + ICB.

项目 1 摘要（子宫颈）局部晚期宫颈癌的护理标准 (SOC)、盆腔放射 (RT) 联合顺铂、失败率高达 30-50%，而且大多数宫颈癌无法治愈。由人乳头瘤病毒 (HPV) 感染引起，HPV 癌基因的持续表达支持临床前研究表明，肿瘤是一种由巨噬细胞介导的慢性间质炎症状态。相关巨噬细胞 (TAM) 是放疗后肿瘤微环境 (TME) 中最丰富的细胞类型并表现出抑制抗肿瘤免疫发展的“M2样”表型。我们证明了治疗前正电子发射时宫颈肿瘤 18F-氟脱氧葡萄糖 (FDG) 的摄取断层扫描 (PET) 与宫颈 TME 中具有“M2 样”表型的 TAM 增加有关，并且用 TAM 培养宫颈肿瘤细胞会增加肿瘤细胞的葡萄糖摄取，我们认为 TAM 与肿瘤有关。 TME 中的细胞共同进化并相互调整其葡萄糖和 ROS 代谢，以优化肿瘤生长。在这个提议中，我们将测试以下假设：SOC CRT 会诱导 ROS 介导的“代谢开关”，从而改变每种细胞类型中的基因转录和代谢，提供限制这种代谢的治疗机会我们通过促进 RT 诱导的抗肿瘤免疫来改善 SOC CRT 后的相互依赖性并改善结果。将结合最先进的单细胞和人类肿瘤的空间分辨分析状态成像以确定 SOC CRT 诱导肿瘤细胞代谢变化的影响 TAM 对 CRT 敏感性进行评估，并进行机械临床前研究以确定这如何影响在目标 1 中，我们将确定 SOC CRT 对抗肿瘤免疫的纵向影响。我们的初步数据支持靶向 CRT。诱导肿瘤细胞中 SOD2 和 NRF2 的上调我们将研究 CRT 相关的 ROS 和 NRF2 变化。在目标 2 中，我们将使用肿瘤类器官和新型小鼠模型来确定线粒体代谢的影响。 SOC CRT 对 TAM 和宫颈 TME 中 T 细胞表型和功能的影响我们将研究 TAM 的影响。 In Aim 3 使用新型成像方法、抗体耗竭和 CCR2 抑制剂进行靶向治疗。我们将 PET 成像特征的纵向变化与 CRT 相关的基因表达变化相结合为了改进患者分类和反应预测，在这些研究中，除了 64Cu- 之外，我们还将使用 FDG。 DOTA-ECLi，一种用于 CCR2+ TAM 的新型 PET 示踪剂最后，我们将与来自我们培训核心的学员一起工作。 METEORITE，优先考虑人类数据中的新线索。该实习生将探索免疫的贡献。众所周知，检查点封锁（ICB）添加到 SOC CRT 中会改变免疫细胞的代谢。我们将综合我们的数据和方法来实现我们的最终目标，即整合这些实验将优化新的治疗方法。组合重编程 TAM 代谢作为改善 SOC CRT + ICB 后结果的新方法。