This project consists of both (1) the technical development of novel bioengineering methods for non-invasive imaging of metabolite transport and metabolism and (2) the application of these methods to study cancer biology. The non-invasive imaging is based on the emerging field of hyperpolarized MRI, which is providing valuable new metabolic information for cancer imaging applications. Using this technique, we are able to greatly increase the MR signal of injected substrates, facilitating the ability to acqure fast metabolic data in seconds. The translation potential of this technique has been demonstrated by the first clinical trial in prostate cancer patients with hyperpolarized pyruvate recently completed by our group. Unlike previous hyperpolarized imaging methods, which only probe metabolic conversions, the proposed projects use diffusion-weighted imaging in order to additionally characterize transport of pyruvate and its metabolic product, lactate. This is of grea biomedical importance since the transport of lactate out of cells has promise for predicting aggressiveness of cancer, progression to metastatic disease and response to therapy, as this creates an acidic environment. There are currently no non-invasive imaging methods to measure metabolite transport in vivo. The developments in this proposal are designed specifically to provide and test such methods. This proposal includes cell studies to measure the mechanisms of cellular transport-mediated contrast, preclinical studies to evaluate diffusivity as a biomarker for transport and metabolism in vivo, and development of a novel hyperpolarized diffusion-weighted imaging method that can be translated into the clinical setting for improved characterization of tumor aggressiveness. Both the cell and preclinical studies also require development of specialized hyperpolarized 13C diffusion-weighted methods because, unlike conventional MRI, the signal decay is rapid and unrecoverable. These studies will use cancer cells and cancer models to evaluate tumor characterization capabilities, and the results will be used to design an optimized clinical protocol, which will be validated through preclinical studies. The proposed novel techniques have the potential to transform tumor characterization through improved prediction of aggressiveness and progression to metastatic disease.
This project will develop and test new metabolite diffusion MRI methods to non-invasively measure metabolism and cellular transport. Both of these mechanisms are highly implicated in aggressive types of cancer, as well as other diseases such as kidney failure and non-alcoholic fatty liver disease. This method has significant potential to improve healthcare by better characterizing disease severity and improving outcome predictions following treatment.
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