Imaging Prostate Cancer Immune Evasion using Chemical Exchange Saturation Transfer MRI

使用化学交换饱和转移 MRI 对前列腺癌免疫逃避进行成像

• 批准号: 10375374
• 负责人: Aline Thomas
• 金额: $ 13.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375374
• 关键词: Applications Grants; Award; Binding; Biological Markers; Biological Process; Biomedical Engineering; Cancer Patient; Cancerous; Cell Line; Cell physiology; Cells; Chemicals; Collaborations; Color; DU145; Data; Disease; Evolution; Failure; Financial compensation; Flow Cytometry; Functional disorder; Genetic; Glutamine; Goals; Grant; Histology; Human; Image; Imaging technology; Immune; Immune Evasion; Immunity; Immunologic Monitoring; Immunologics; Immunosuppression; Immunotherapy; In Vitro; Infiltration; LNCaP; Label; Learning; Leukocytes; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Modeling; Monitor; Natural regeneration; Optical Methods; PC3 cell line; Play; Preparation; Prostate; Protons; Regimen; Reporter Genes; Research; Research Personnel; Safety; Salicylic Acids; Scheme; Signal Transduction; Surface; Testing; Therapeutic; Training; Translating; Translations; Tumor Escape; Tumor Immunity; Tumor-infiltrating immune cells; Validation; Work; base; biomaterial compatibility; cancer therapy; career; cell behavior; clinically translatable; cytokine; design; detection method; imaging agent; imaging biomarker; imaging detection; in vivo; insight; molecular imaging; mouse model; new technology; non-invasive imaging; patient response; programmed cell death ligand 1; programs; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; quantitative imaging; radio frequency; spatiotemporal; success; symposium; therapeutic gene; treatment response; tumor; tumor progression; uptake

Immunotherapy is a promising strategy for cancer patients, particularly for those nonresponsive to more conventional therapeutic regimens. Quantitative imaging of immune evasion biomarkers can help identify patients responsive to immunotherapy. Chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) is a molecular imaging technology that is already being translated to humans. CEST MRI has the unique ability to monitor multiple agents simultaneously through selectively labeling their exchangeable protons with radiofrequency saturation, which can be encoded as “colors” similar to optical methods. We propose to develop (1) agents with unique colors and (2) analysis methods to quantify these agents and generate multicolor MR images. This award will support Dr. Aline Thomas in her transition to an independent research career. Candidate Training: Dr. Thomas has a background in biomedical engineering, investigating factors contributing to pathophysiology and regeneration failure in disease settings with an immune component using material, computational, genetic (therapeutic and reporter genes), and through collaboration, conventional MRI methods. With the guidance of her mentors, Dr. Thomas will learn how to develop clinically translatable CEST agents and quantify their targets using post-processing methods to probe multiple cellular processes in vivo in order to monitor cell behavior in disease and in response to therapy. She will also be trained in the practical aspects of a leading a research program—lab management, trainee mentorship, conference presentation, networking and fundraising—which are critical to her success as an independent investigator in the field of Molecular Imaging. The proposed work will lead to the preparation of a R01 grant proposal. Research Plan: A recognized mechanism of cancer to evade immunological attack is glutamine transport to deactivate (via PD- L1) and to deprive energy (independent of PD-L1) from infiltrating immune cells. The central hypothesis is that quantitative imaging of immune evasion mechanisms using CEST MRI can ultimately be used to help predict patient response to immunotherapy. Dr. Thomas proposes to develop CEST MRI agents and detection methods that can quantify glutamine transport and PD-L1 expression simultaneously. She will also develop post-processing methods to quantify these agents. To validate their potential as complementary imaging biomarkers of cancer immune evasion, she will evaluate their uptake in prostate cancer cell lines (in vitro; cancerous: PC3, LNCaP, DU-145; noncancerous: RWPE-1 and RWPE-2) and in a prostate tumor model (in vivo) and compare their uptake to conventional immune suppression (PD-L1 histology, flow cytometry, cytokines) and immune evasion (surface marker expression, tumor infiltration of leukocytes) metrics. Aim 1: Develop methods to visualize and quantify PD-L1 expression in prostate cancer. Aim 2: Develop methods to visualize and quantify glutamine transport in prostate cancer. Aim 3: Validate the methods by evaluating both PD-L1 expression and glutamine transport simultaneously in prostate cancer progression models.

免疫疗法对于癌症患者来说是一种有前途的策略，特别是对于那些对更多药物无反应的患者 常规治疗方案。免疫逃避生物标志物的定量成像可以帮助识别 对免疫治疗有反应的患者。化学交换饱和转移磁共振成像 (CEST MRI) 是一种分子成像技术，已应用于人类。 CEST MRI 有 通过选择性标记可交换质子来同时监测多个试剂的独特能力 具有射频饱和度，可以像光学方法一样编码为“颜色”。我们建议 开发（1）具有独特颜色的试剂和（2）分析方法来量化这些试剂并生成 多色 MR 图像。该奖项将支持艾琳·托马斯博士向独立研究过渡 职业。候选人培训：托马斯博士拥有生物医学工程、调查因素的背景 使用免疫成分导致疾病环境中的病理生理学和再生失败 材料、计算、遗传（治疗和报告基因），并通过合作，传统 MRI 方法。在导师的指导下，Thomas 博士将学习如何开发可临床转化的 CEST 剂并使用后处理方法量化其目标，以探测体内的多个细胞过程 为了监测疾病中的细胞行为以及对治疗的反应。她还将接受实践培训 领导研究项目的各个方面——实验室管理、实习生指导、会议演示、 网络和筹款——这对于她作为该领域的独立调查员的成功至关重要 分子成像。拟议的工作将导致 R01 拨款提案的准备。研究计划：A 公认的癌症逃避免疫攻击的机制是谷氨酰胺转运失活（通过PD- L1) 并剥夺浸润免疫细胞的能量（独立于 PD-L1）。中心假设是 使用 CEST MRI 对免疫逃避机制进行定量成像最终可用于帮助预测 患者对免疫治疗的反应。 Thomas博士提议开发CEST MRI药剂和检测 可以同时量化谷氨酰胺转运和 PD-L1 表达的方法。她还将发展 量化这些试剂的后处理方法。验证它们作为补充成像的潜力 癌症免疫逃避的生物标志物，她将评估它们在前列腺癌细胞系中的摄取（体外； 癌性：PC3、LNCaP、DU-145；非癌性：RWPE-1 和 RWPE-2）和前列腺肿瘤模型（在 体内）并将其摄取与传统免疫抑制（PD-L1 组织学、流式细胞术、 细胞因子）和免疫逃避（表面标志物表达、白细胞肿瘤浸润）指标。目标 1： 开发可视化和量化前列腺癌中 PD-L1 表达的方法。目标 2：开发方法 可视化和量化前列腺癌中的谷氨酰胺转运。目标 3：通过评估两者来验证方法 在前列腺癌进展模型中，PD-L1 表达和谷氨酰胺转运同时进行。