Noninvasive prediction of tumor response to gemcitabine using MRI

Noninvasive prediction of tumor response to gemcitabine using MRI


The prediction of tumor response to chemotherapy can be achieved by elucidating the efficiency of drug delivery to the targeted tumor cells, and the effectiveness of the delivered drug to be activated and act on tumor cells. A non-invasive means that can answer these questions is essential for designing efficient and personalized therapy, and is especially crucial to improve the efficacy of treating pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human malignancies. In the present study, we propose to develop a highly translatable MRI technology to answer the two questions mentioned above in the gemcitabine treatment of PADC, and hence to predict tumor responses. In particular, Our approach is based on a so-called Chemical Exchange Saturation Transfer (CEST) MRI contrast mechanism, by which drugs are imaged directly by their inherently carried exchangeable protons (OH, NH or NH2), at a detectability comparable to that for Gd-based agents. Formulated on the basis of our preliminary results, we hypothesize that agents that contain cytosine and cytidine, for instance gemcitabine, can be detected using CEST MRI, namely cytCEST. We anticipate our approach can be used to predict tumor response to the gemcitabine treatment by assessing the accumulation, biodistribution and retention of the drug in the tumor, without the need for imaging tags or additional agents. To achieve our goal, we will first optimize and validate the cytCEST MRI detection of tumor uptake and biodistribution of gemcitabine. Then we will develop cytCEST MRI as an effective means to detect the activity of deoxycytidine kinase (dCK), one of the most important drug-resistance-related enzymes. Finally the potential of cytCEST MRI to predict the response of pancreatic tumors to therapy will be examined on the treatment in KPC genetically engineered mouse models using three different gemcitabine-based treatments. Successful completion of this project will result in an imaging tool for the prediction of tumor response to gemcitabine using the drug or its analog deoxycytidine directly as the imaging agent, namely label-free because no chemical-modification is needed. It is expected that such a label-free approach can be rapidly translated to the clinic, allowing clinicians to stratify patients prior to (or immediately after) the administration of gemcitabine or other cytosine- or cytidine-based chemotherapeutic drugs and to choose the personalized treatment plan for each group of patients.

Public Health Relevance

The project is relevant to public health because it is expected to result in a highly translatable medical imaging technology for non-invasively and early predicting the response of tumors, for instance pancreatic ductal adenocarcinoma (PDAC), to a gemcitabine-based chemotherapy. This proposed technology directly detect gemcitabine or its analog deoxycytidine using a technique called chemical exchange saturation transfer (CEST), without the need for extra chemical-, paramagnetic-, or radioactive- imaging labeling. It is expected that the proposed label-free approach, once established, can be rapidly translated to the clinic, allowing clinicians to stratify patients prior to (or immediately after) the administration of gemcitabine or other cytidine-based chemotherapeutic drug and to choose an appropriate treatment plan in the manner of personalized medicine.


Bar-Shir A, Liu G, Greenberg MM, Bulte JW, Gilad AA. “Synthesis of a probe for monitoring HSV1-tk reporter gene expression using chemical exchange saturation transfer MRI.” Nat Protoc. 2013 Dec;8(12):2380-91. doi: 10.1038/nprot.2013.140. Epub 2013 Oct 31.
Bar-Shir A, Liu G, Chan KW, Oskolkov N, Song X, Yadav NN, Walczak P, McMahon MT, van Zijl PC, Bulte JW, Gilad AA. “Human protamine-1 as an MRI reporter gene based on chemical exchange.” ACS Chem Biol. 2013 Oct 25. [Epub ahead of print].
Liu G, Bettegowda C, Qiao Y, Staedtke V, Chan KW, Bai R, Li Y, Riggins GJ, Kinzler KW, Bulte JW, McMahon MT, Gilad AA, Vogelstein B, Zhou S, van Zijl PC. “Noninvasive imaging of infection after treatment with tumor-homing bacteria using Chemical Exchange Saturation Transfer (CEST) MRI.” Magn Reson Med. 2013 Dec;70(6):1690-8. doi: 10.1002/mrm.24955. Epub 2013 Oct 7.
Bar-Shir A, Gilad AA, Chan KW, Liu G, van Zijl PC, Bulte JW, McMahon MT. “Metal ion sensing using ion chemical exchange saturation transfer 19F magnetic resonance imaging.” J Am Chem Soc. 2013 Aug 21;135(33):12164-7. doi: 10.1021/ja403542g. Epub 2013 Aug 6.
Yang X, Song X, Li Y, Liu G, Ray Banerjee S, Pomper MG, McMahon MT. “Salicylic acid and analogues as diaCEST MRI contrast agents with highly shifted exchangeable proton frequencies.” Angew Chem Int Ed Engl. 2013 Jul 29;52(31):8116-9. doi: 10.1002/anie.201302764. Epub 2013 Jun 21. No abstract available.

Research summary

Liu Group’s current research projects focus on the development and applications of a novel MRI technique, chemical exchange saturation transfer (CEST). His team is currently developing a variety of nanoparticle-based CEST imaging probes with low toxicity, high sensitivity and high specificity, and exploring the biomedical applications of these new imaging probes. In addition, the team is also interested in exploring the biomedical uses of endogenous CEST contrast; one of their ongoing projects examines the use of the endogenous CEST MRI signal of bacterial organisms to detect and monitor bacterial infection in rodent models.