Combined biochemical and biophysical imaging biomarkers for characterization of tumor metabolism and response to therapy

成像生物标记物能够对组织进行全面的表征，提供解剖结构以外的功能、生理、代谢、细胞和分子信息。对于癌症患者，用于早期检测、肿瘤表型鉴定和治疗反应评估的特定非侵入性成像策略尚未达到令人满意的水平，这产生了对先进技术的迫切需求。在这个项目中，我的目标是开发两种新的非侵入性成像技术来测量肿瘤的细胞外pH和跨膜透水性。首先，通过pH成像，我们想要表征由异常代谢引起的酸性肿瘤微环境，并研究其与肿瘤侵袭性和肿瘤治疗反应之间的联系。其次，我们将测试跨膜水渗透成像是否报告了细胞死亡的早期阶段，从而提供了一种早期评估技术，在解剖上肿瘤大小缩小可识别之前，检测药物是否已击中目标。具体地说，我们将使用新型超极化13C标记生物传感器和用于3D pH成像的新的MRI采集方案来推进现有的非侵入性MRI pH成像方法。将开发更快、更灵敏的跨膜水交换磁共振成像体外和体内测量方案，从而能够绘制表观交换率(AXR)的3D图谱。PH成像和AXR标测都可以帮助阐明肿瘤生物学，从而能够非侵入性地表征肿瘤的代谢表型和检测早期治疗反应。

Imaging biomarkers enable a comprehensive characterization of tissue providing functional, physiological, metabolic, cellular and molecular information beyond anatomical structures. For cancer patients, specific non-invasive imaging strategies for early-stage detection, tumor phenotyping and evaluation of response to therapy are not available at a satisfactory level, creating a pressing need for advanced technologies. In this project, I aim to develop two novel non-invasive imaging techniques to measure extracellular pH and transmembrane water permeability in tumors. First, by using pH imaging, we want to characterize the acidic tumor microenvironment caused by aberrant metabolism and study the link to tumor aggressiveness and tumor response to treatment. Second, we will test whether imaging of transmembrane water permeability reports on early stages of cell death, thereby providing an early evaluation technology to detect whether a drug has hit its target before an anatomical reduction in tumor size is recognizable. Specifically, we will advance current methods for non-invasive MRI pH imaging using novel hyperpolarized 13C-labelled biosensors and new MRI acquisition schemes for 3D pH imaging. Faster and more sensitive protocols for transmembrane water exchange MRI measurements in vitro and in vivo will be developed allowing 3D mapping of the apparent exchange rate (AXR). Both pH imaging and AXR mapping can help to elucidate tumor biology, allowing to characterize tumor metabolic phenotype and to detect early treatment response non-invasively.