Established guidelines for assessing response of solid tumors to therapy are based on conventional imaging indices, such as tumor size and vascularity, and were intended to facilitate a uniform assessment of response to systemically administered chemotherapeutics that target proliferating cells in a well-perfused microenvironment. An emerging imaging phenotype of tumor recurrence indicates that a complete radiographic response may be followed by variable periods of latency without perceptible growth in poorly perfused microenvironments. This imaging phenotype highlights the capability of cancer cells to adapt their growth program to their microenvironment and effect tumor dormancy and underscores the importance of developing functional imaging paradigms to enable their detection. Transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) provides a compelling clinical correlate to this imaging deficiency. TACE exploits the vascular biology of HCC to deprive tumors of nutrients, leading to necrosis; however, only 44% of large treated lesions demonstrate extensive necrosis on pathology, underscoring the adaptive response of HCC cells to nutrient deprivation. This adaptive response is reflected by the presence of viable tumor cells adjacent to regions of necrosis on histopathology, and is consistent with the rapid recurrence following a period of latency often observed on follow-up imaging. In preclinical studies, we demonstrated that: 1) HCC cells surviving TACE-induced ischemia are reprogrammed to shunt glucose carbons toward lactate, providing a unique signature for the detection of these cells; 2) based on this reprogramming, Dynamic Nuclear Polarization Magnetic-13Carbon-Magnetic Resonance Spectroscopic Imaging (DNP-13C-MRSI)of hyperoplarized (HP) 1-13C-pyruvate enables the more sensitive detection of HCC cells for response assessment to TACE as compared to standard-of-care (SOC) MRI; and 3) the detection of TACE-refractory cellular domains will inform targeted therapy by identifying molecular dependencies. We hypothesize that DNP-13C-MRSI of HP 1-13C-pyruvate provides a unique technology through which to leverage the metabolic reprogramming in HCC cells surviving TACE and enable functional molecular imaging for effective treatment response assessment in patients. To test this hypothesis the proposed project will pursue two primary aims: (1) to validate an optimized pulse sequence for in vivo hepatic arterial phase DNP-13C-MRSI of HP 1-13C-pyruvate in HCC using clinical imaging systems.; (2a) to determine the sensitivity of DNP-13C-MRSI of HP 1-13C-pyruvate uptake and metabolism for identifying local recurrence in patients with a complete response to TACE, as measured by current SOC imaging response criteria; and (2b) to determine the accuracy of DNP- 13C-MRSI of HP 1-13C-pyruvate to lactate and alanine for the detection of the targetable metabolic stress response in HCC cells following TACE. The achievement of t...