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.