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. The development of functional measures of this altered tumor metabolism is critical to effective preclinical and clinical imaging of response. Trans-arterial 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 that is often discovered on follow-up imaging. Thus, TACE provides a useful model for identifying the mechanisms mobilized by cancer cells to survive severe ischemia. In preliminary studies, we have demonstrated that TACE-like severe ischemia induces quiescence in surviving cells and that these cells activate a metabolic stress response (MSR) including hypoxia-inducible factors, the unfolded protein response and autophagy, which reprogram metabolism to enable survival under ischemic conditions. The recent development of Dynamic Hyperpolarized Carbon-13 Nuclear Magnetic Resonance spectroscopy and spectroscopic imaging (DNP-13C-NMRS) has yielded promising results in studies of metabolism in hepatocellular disease. This technology represents a unique resource to translate advances in our understanding of the MSR into a non-invasive, clinically applicable imaging paradigm to identify dormant cancer cells surviving ischemia. The conventional post-TACE imaging phenotype of sustained survival without proliferation under metabolic stress will be examined using targeted metabolomics, proteomic and epigenetic profiling of HCC cells to develop a DNP-13C-NMRS based imaging approach. The primary objectives of this application are to: a) characterize the nutrient microenvironment as well as the epigenetic and proteomic alterations underlying MSR-induced metabolic adaptation in cells surviving ischemic stress, b) develop a DNP- 13C-NMRS based metabolic imaging approach to enable the non-invasive detection of cells surviving ischemic stress in vitro, and c) translate this approach to characterize cells surviving trans-arterial embolization in vivo.

Public Health Relevance

Cancer cells can adapt their metabolism to survive the severe metabolic stress caused by current treatments. Available imaging techniques cannot detect these surviving cells. By combining a better understanding of how surviving cancer cells adapt with novel imaging technology, this study will take important steps toward the development of clinical imaging that can detect surviving cancer cells.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Early Independence Award (DP5)
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Special Emphasis Panel ()
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Basavappa, Ravi
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University of Pennsylvania
Schools of Medicine
United States
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