Application of hyperpolarized 13C interstitial pH imaging to risk stratification in prostate cancer

超极化 13C 间质 pH 成像在前列腺癌风险分层中的应用

• 批准号: 9888209
• 负责人: Robert Richard Flavell
• 金额: $ 15.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888209
• 关键词: Acidity; Androgens; Animal Model; Bicarbonates; Biological; Biological Markers; Carbonates; Clinical; Data; Detection; Disease; Disease Outcome; Disease Progression; Engineering; Event; Exclusion; Genetically Engineered Mouse; Glycerol; Goals; Growth and Development function; Histologic; Human; Hydrolysis; Image; Investigational Drugs; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Measures; Metastatic Neoplasm to the Liver; Methods; Modeling; Molecular; Neoplasm Metastasis; Noise; Oncogenic; Operative Surgical Procedures; PTEN gene; Pathologic; Pathway interactions; Patients; Pharmacology; Phase I Clinical Trials; Physiologic pulse; Preparation; Production; Prostate; Prostate Adenocarcinoma; Prostatic Neoplasms; Protocols documentation; Quality Control; Resolution; Risk stratification; Role; Signal Transduction; Staging; Sterility; Techniques; Testing; Transgenic Organisms; Translations; clinical translation; clinically relevant; clinically translatable; cohort; deprivation; experimental study; first-in-human; high resolution imaging; imaging biomarker; imaging modality; improved; insight; interstitial; lymph nodes; men; mouse model; outcome forecast; prognostic; prostate cancer model; prostate cancer risk; transgenic adenocarcinoma of mouse prostate; tumor; tumor growth

PROJECT SUMMARY The central aim of this proposal is to apply a method for high resolution imaging of interstitial pH using hyperpolarized 13C magnetic resonance imaging to the detection of aggressive, potentially lethal disease in prostate cancer. We have very recently developed a method for production of a highly concentrated and polarized solution of hyperpolarized 13C bicarbonate through polarization of a precursor, glycerol carbonate, and subsequent hydrolysis. This method overcomes many of the limitations of previously described pH imaging methods and has a strong potential to allow for clinical translation. Prostate cancer presents with a heterogeneous disease course, and there is an urgent unmet clinical need for improved biomarkers for the detection or exclusion of aggressive, potentially lethal disease. One potential prognostic imaging biomarker in prostate cancer is acidic interstitial pH, which is associated with local invasion and metastases in animal models in a variety of cancers. Thus, a high resolution, clinically translatable method of imaging interstitial pH would have significant impact and could find immediate utility in initial staging of men with low or intermediate risk prostate cancer. The goal of this proposal is to test the ability of a recently developed hyperpolarized 13C magnetic resonance imaging method targeting interstitial acidity to predict high grade disease and subsequent progression in murine models of prostate cancer, and to develop suitable production and quality control methods for subsequent clinical translation. In specific aim 1, the correlation between interstitial acidity, high grade disease, and disease progression is studied in the transgenic adenocarcinoma of the prostate (TRAMP) animal model. In specific aim 2, this correlation is further validated in new, more clinically relevant models of prostate cancer, and the fundamental molecular mechanisms underpinning interstitial acidity are studied through pharmacologic modulation of various pathways. In specific aim 3, the production and imaging methods are optimized and suitable quality control measures are generated for subsequent clinical translation. If completed, the experiments outlined in this proposal would cement interstitial acidity as an imaging biomarker for aggressive, potentially lethal prostate cancer in animal models, elucidate molecular mechanisms underlying the phenomenon, and set the stage for subsequent clinical translation in men with prostate cancer.

项目概要 该提案的中心目标是应用一种使用间隙 pH 值进行高分辨率成像的方法 超极化 13C 磁共振成像可用于检测侵袭性、潜在致命性疾病 前列腺癌。我们最近开发了一种生产高度浓缩和 通过前体碳酸甘油酯的极化获得超极化 13C 碳酸氢盐的极化溶液， 以及随后的水解。该方法克服了先前描述的 pH 值的许多限制 成像方法，具有很强的临床转化潜力。前列腺癌表现为 疾病过程异质性，并且对改进的生物标志物的迫切未满足的临床需求 检测或排除侵袭性、潜在致命的疾病。一种潜在的预后成像生物标志物 前列腺癌间质pH呈酸性，与动物的局部侵袭和转移有关 多种癌症模型。因此，一种高分辨率、临床可转化的间质 pH 成像方法 将会产生重大影响，并且可以在低度或中度男性的初始阶段立即发挥作用 有患前列腺癌的风险。 该提案的目标是测试最近开发的超极化 13C 磁性材料的能力 针对间质酸度的共振成像方法可预测高度疾病和后续疾病 前列腺癌小鼠模型的进展，并开发合适的生产和质量 后续临床转化的控制方法。在具体目标 1 中，插页式广告之间的相关性 在转基因腺癌​​中研究了酸度、高度疾病和疾病进展 前列腺（TRAMP）动物模型。在具体目标 2 中，这种相关性在新的、更具临床意义的研究中得到了进一步验证。 前列腺癌的相关模型以及间质的基本分子机制 酸度是通过各种途径的药理调节来研究的。在具体目标 3 中，生产 优化成像方法并为后续生成合适的质量控制措施 临床翻译。如果完成，本提案中概述的实验将巩固间质酸度 动物模型中侵袭性、可能致命的前列腺癌的成像生物标志物，阐明了分子生物学 该现象背后的机制，并为随后在男性中的临床转化奠定了基础 前列腺癌。

项目成果

Amino Acid-Derived Sensors for Specific Zn2+ Detection Using Hyperpolarized 13 C Magnetic Resonance Spectroscopy.

使用超极化 13 C 磁共振波谱进行特定 Zn2 检测的氨基酸衍生传感器。

• DOI: 10.1002/chem.201902771
• 发表时间: 2019
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Wang,Sinan;Korenchan,DavidE;Perez,PaolaM;Taglang,Céline;Hayes,ThomasR;Sriram,Renuka;Bok,Robert;Hong,AndrewS;Wu,Yunkou;Li,Henry;Wang,Zhen;Kurhanewicz,John;Wilson,DavidM;Flavell,RobertR
• 通讯作者: Flavell,RobertR