Anaplastic thyroid cancer (ATC) is an aggressive malignancy, which accounts for approximately 50% of all thyroid cancer related deaths. Current treatment paradigms rely on ionizing radiation (IR) as a primary means of achieving locoregional control. As such, development of novel radiosensitizing agents is of crucial importance in the management of this deadly disease. Clinical implementation of novel radiosensitizing strategies has been hampered by an inability to perform detailed mechanistic studies of IR effects on tumor biology in vivo in real time. We have recently demonstrated that hyperpolarized magnetic resonance spectroscopy (HP-MRS) can be used to detect perturbations in tumor metabolism following targeted pharmacologic inhibition and exposure to IR. Here we propose to use HP-MRI to evaluate tumor response to the radiosensitizing effects of anti-metabolic drugs. This imaging modality will be utilized in the context of a previously developed integrated preclinical model of anaplastic thyroid carcinoma (ATC). Ionizing radiation (IR) induces tumor cell death primarily through the formation of reactive oxygen species (ROS). Tumor cell resistance to IR is driven in large part by the ability to generate sufficient reducing equivalents to neutralize ROS. Pharmacologic inhibition of tumor metabolic pathways can decrease reducing equivalent levels and potentiate ROS generation in response to IR. In this study we will define and refine a metabolically based radiosensitization strategy broadly applicable across multiple ATC cell lines. To date it has not been possible to evaluate the effects of anti-metabolic agents on tumor reducing potential in vivo in a manner designed to maximize radiosensitization. For the first time, we propose to use HP-MRS to ascertain and optimize the effectiveness of a metabolically based radiosensitization strategy. Completion of this study is expected to achieve two specific goals. First, it will begin to define the therapeutic viability of this type of a radiosensitizatio approach. Second, it will further demonstrate the potential of HP-MRS to refine the implementation of radiosensitization strategies in general and to tailor the administration of IR t solid tumors. Never before have clinicians been able to measure IR effectiveness during treatment and potentially alter treatment decisions in real-time. The experiments proposed below represent a critical first step towards attaining that ability and providing a new paradigm for therapeutic regimen design in ATC and other solid tumors.
Anaplastic thyroid cancer (ATC) is one of the most lethal human diseases and current treatment options are largely ineffective. This proposal evaluates the potential of hyperpolarized magnetic resonance spectroscopy (HP-MRS) to assist in the optimization of a metabolically based radiosensitization strategy for ATC.
|Yu, Wangie; Chen, Yunyun; Dubrulle, Julien et al. (2018) Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism. Sci Rep 8:4306|
|Sun, Chang-Yu; Walker, Christopher M; Michel, Keith A et al. (2018) Influence of parameter accuracy on pharmacokinetic analysis of hyperpolarized pyruvate. Magn Reson Med 79:3239-3248|
|Sandulache, Vlad C; Chen, Yunyun; Feng, Lei et al. (2017) Metabolic interrogation as a tool to optimize chemotherapeutic regimens. Oncotarget 8:18154-18165|
|Joint Head and Neck Radiotherapy-MRI Development Cooperative (2016) Dynamic contrast-enhanced MRI detects acute radiotherapy-induced alterations in mandibular microvasculature: prospective assessment of imaging biomarkers of normal tissue injury. Sci Rep 6:29864|
|Walker, Christopher M; Chen, Yunyun; Lai, Stephen Y et al. (2016) A novel perfused Bloch-McConnell simulator for analyzing the accuracy of dynamic hyperpolarized MRS. Med Phys 43:854-64|
|Walker, Christopher M; Merritt, Matthew; Wang, Jian-Xiong et al. (2016) Use of a Multi-compartment Dynamic Single Enzyme Phantom for Studies of Hyperpolarized Magnetic Resonance Agents. J Vis Exp :e53607|
|Sandulache, Vlad C; Chen, Yunyun; Skinner, Heath D et al. (2015) Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model. Mol Cancer Ther 14:2901-8|
|Bankson, James A; Walker, Christopher M; Ramirez, Marc S et al. (2015) Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors. Cancer Res 75:4708-17|
|Lai, Stephen Y; Fuller, C David; Bhattacharya, Pratip K et al. (2015) Metabolic Imaging as a Biomarker of Early Radiation Response in Tumors. Clin Cancer Res 21:4996-8|
|Johnson, Jennifer M; Lai, Stephen Y; Cotzia, Paolo et al. (2015) Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer. Semin Oncol 42:915-22|
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