The objective of this proposed R21 grant is to demonstrate the application of hyperpolarized C-13 MR metabolic imaging as a new and unique tool for detecting early response to therapy in patients with glioma. Translating this novel and exciting technology into the clinic is of particular interest for studying these tumors because the are heterogeneous on conventional anatomic images and it is often difficult to interpret changes that occur in response to therapy. The population being considered will comprise 20 adult patients who have received a subtotal surgical resection with a diagnosis of grade 4 glioma (GBM). Sterile hyperpolarized C-13 pyruvate will be prepared using the proof of concept DNP polarizer adjacent to our research 3T MR scanner. Patients will be scanned prior to initiating therapy (baseline) and within 4 weeks after starting therapy (early follow-up) using a research MR imaging protocol that includes anatomic, diffusion, perfusion and lactate-edited H-1 spectroscopic images, as well as the acquisition of hyperpolarized C-13 metabolic data. Post-processing will use custom-designed software to estimate the time course of changes in levels of lactate/pyruvate and to relate them to abnormalities observed in the other MR images. The first 10 patients will be scanned using a dynamic 2-D C-13 EPSI sequence in order to track the time course of delivering C-13 pyruvate to the tumor and its conversion to lactate. The next 10 patients will be studied with a single 3-D C-13 EPSI sequence starting at the time expected to give the highest contrast to noise for lactate/pyruvate in tumor versus normal brain. These data will be analyzed to address two aims.
Specific Aim 1 : To compare the ratio of lactate/pyruvate for regions of residual tumor vs normal brain. We hypothesize that patients with GBM have elevated hyperpolarized C-13 lactate/pyruvate at baseline in regions of the residual T2 hyperintensity (T2L) compared to levels in normal brain Specific Aim 2: To determine whether patients exhibit a reduction in lactate/pyruvate with therapy. We will test the hypothesis that subjects receiving treatment with radiation and temozolomide will exhibit a reduction in hyperpolarized C-13 lactate/pyruvate at early follow-up compared to their baseline scan. The outcome of this study will be the availability of a rapid and sensitive metabolic imaging method that will help in clinical decision-making by providing a more reliable characterization of response to therapy that will help to determine whether alternative strategies are required.

Public Health Relevance

Optimizing treatment for patients with glioma is complicated by heterogeneity within and between lesions, as well as by the ambiguities in interpreting response to therapy using standard imaging methods. The goal of the proposed study is to demonstrate the application of hyperpolarized C-13 MR metabolic imaging as a new and unique tool for detecting early response to therapy for patients with GBM.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-W (56))
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Henderson, Lori A
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Park, Ilwoo; Larson, Peder E Z; Gordon, Jeremy W et al. (2018) Development of methods and feasibility of using hyperpolarized carbon-13 imaging data for evaluating brain metabolism in patient studies. Magn Reson Med 80:864-873
Park, Ilwoo; von Morze, Cornelius; Lupo, Janine M et al. (2017) Investigating tumor perfusion by hyperpolarized 13 C MRI with comparison to conventional gadolinium contrast-enhanced MRI and pathology in orthotopic human GBM xenografts. Magn Reson Med 77:841-847
Park, I; Nelson, S J; Talbott, J F (2016) In Vivo Monitoring of Rat Spinal Cord Metabolism Using Hyperpolarized Carbon-13 MR Spectroscopic Imaging. AJNR Am J Neuroradiol 37:2407-2409
Park, Ilwoo; Larson, Peder E Z; Tropp, James L et al. (2014) Dynamic hyperpolarized carbon-13 MR metabolic imaging of nonhuman primate brain. Magn Reson Med 71:19-25
Nelson, Sarah J; Ozhinsky, Eugene; Li, Yan et al. (2013) Strategies for rapid in vivo 1H and hyperpolarized 13C MR spectroscopic imaging. J Magn Reson 229:187-97