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

项目摘要 该建议的中心目的是应用一种方法，用于高分辨率成像的间质pH值， 超极化13C磁共振成像检测侵袭性，潜在的致命性疾病， 前列腺癌我们最近开发了一种生产高度浓缩的， 通过前体，碳酸甘油酯， 和随后的水解。该方法克服了先前描述的pH的许多限制。 成像方法，并具有很强的潜力，使临床翻译。前列腺癌的症状有哪些 因此，对于异质性疾病过程的改善的生物标志物存在迫切的未满足的临床需求。 检测或排除侵袭性、潜在致命性疾病。一种潜在的预后成像生物标志物， 前列腺癌是酸性间质pH，其与动物中的局部浸润和转移相关 各种癌症的模型。因此，一种高分辨率、临床上可翻译的间质pH成像方法， 将有显着的影响，并可能发现在初始阶段的低或中等男性的直接效用 患前列腺癌的风险。 该提案的目的是测试最近开发的超极化13C磁 靶向间质酸度的共振成像方法，用于预测高级别疾病和随后的 在前列腺癌小鼠模型中的进展，并开发合适的生产和质量 后续临床翻译的控制方法。在具体目标1中， 酸性，高级别疾病和疾病进展的研究是在转基因腺癌的， 前列腺（TRAMP）动物模型。在具体目标2中，这种相关性在新的、更临床的研究中得到进一步验证。 前列腺癌的相关模型，以及支持间质性前列腺癌的基本分子机制， 酸度是通过药理学调节各种途径进行研究的。具体目标3： 并优化成像方法，并为后续的质量控制措施生成合适的质量控制措施。 临床翻译如果完成，该提案中概述的实验将巩固间隙酸性， 在动物模型中，作为侵袭性、潜在致死性前列腺癌的成像生物标志物， 这一现象背后的机制，并为随后在男性中的临床翻译奠定了基础。 前列腺癌

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.