Hyperpolarized 13C Magnetic Resonance Spectroscopy: Probing Enzymatic Activity, Cellular Transport, and Oncogene Activation

Magnetic resonance spectroscopy (MRS) of hyperpolarized (HP) substrates is a powerful tool to investigate tissue metabolism in vivo. Recently, a first-in-man clinical trial of this technology showed feasibility, safety, and great promise for noninvasive diagnosis of cancer via the detection of previously unobservable phenomena such as the Warburg Effect. However, the acquired signal is a combination of flow, perfusion, diffusion, and relaxation in addition to metabolism. To isolate these effects and provide improved measurement of metabolic alterations in cancer, I designed tailored acquisition and reconstruction techniques. These techniques rely on the phase accumulation from stimulated echoes to "tag" metabolites and compressed sensing data undersampling to optimize acquisition time and resolution, thus allowing for the accurate, non-invasive measurement and localization of enzymatic activity, cellular transport, and oncogene activation. Specifically, we detected high enzymatic activity of lactate dehydrogenase (LDH) in high-grade regions within primary tumors and metastatic lesions in a transgenic prostate cancer tumor model. We also observe increased efflux of lactate via monocarboxylate transporter 4 (MCT4), which is upregulated in aggressive subsets of a number of cancers and may correlate with metastatic potential. We also detected the presence of the h-Ras oncogene in a switchable oncogene-driven model of liver cancer, which expresses altered oncogene-induced signaling pathways between c-Myc and h-Ras driven cancer models. Notably for oncology in particular, these new techniques have great biomedical and clinical significance, as they could be used to better identify particularly aggressive regions within tumors, monitor cancer progression, follow response to therapy, and improve treatment planning