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

成像生物标志物能够全面表征组织，提供解剖结构之外的功能、生理、代谢、细胞和分子信息。对于癌症患者来说，用于早期检测、肿瘤表型和治疗反应评估的特异性非侵入性成像策略还没有达到令人满意的水平，因此迫切需要先进的技术。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细胞外pH值和跨膜透水性。首先，通过pH成像，我们希望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对治疗的反应之间的联系。其次，我们将测试跨膜透水性成像是否能报告细胞死亡的早期阶段，从而提供一种早期评估技术，在肿瘤解剖缩小之前检测药物是否击中目标。具体来说，我们将利用新型超极化13c标记生物传感器和用于3D pH成像的新型MRI采集方案来推进当前的非侵入性MRI pH成像方法。将开发更快、更灵敏的体外和体内跨膜水交换MRI测量方案，允许对表观交换率（AXR）进行3D测绘。pH成像和AXR定位都可以帮助阐明肿瘤生物学，表征肿瘤代谢表型，并无创地检测早期治疗反应。

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.