Abstract B07: Using magnetic resonance and hyperpolarized tracers to monitor solid tumor progression, metastasis, and response to treatment

Purpose: To optimize translational fidelity of a murine model of anaplastic thyroid carcinoma (ATC) using real-time metabolic imaging. Background: Anaplastic thyroid carcinoma (ATC) is an aggressive solid malignancy with rapid growth, invasion of critical cervical structures and a high rate of pulmonary metastasis. Although rare in overall incidence (2-3% of thyroid cancer), ATC accounts for 50% of thyroid cancer related mortality. The rapid rate of growth and metastasis makes optimization of treatment algorithms challenging and development of novel therapeutic strategies difficult. Our group has developed an integrated preclinical model of ATC using validated human cell lines and a xenograft mouse model which recapitulates disease characteristics and closely mimics response to treatment including chemotherapy and ionizing radiation (IR). Experimental procedures: Validated human ATC cell lines were either injected into the right thyroid lobe of athymic nude mice in an orthotopic tumor model or intravenously (tail-vein) to generate pulmonary metastases. Tumors were exposed to varying doses of ionizing radiation (IR) and monitored using both anatomic magnetic resonance imaging (MRI) sequences as well as hyperpolarized (HP) [1-13C]-pyruvate (PYR). HP-MR data was acquired using either temporal or spatial acquisition sequences depending on the experimental aims. At the completion of intended experiments, primary thyroid tumors and pulmonary metastases were harvested and analyzed using standard histologic and immunohistochemical techniques. Results: We have employed HP-MR using labeled [1-13C]-pyruvate to measure tumor metabolic activity in real-time. We have translated this capability into precise measurements of tumor viability at the primary site, which when combined with anatomic MRI sequences provides enhanced visualization and identification of critical cervical structure invasion. HP-MR has allowed us to identify sub-centimeter pulmonary metastases and differentiate tumor from normal lung parenchyma based on the inherently higher rate of conversion of labeled pyruvate (PYR) into lactate (LAC). We had previously demonstrated that pharmacologic perturbations in tumor reducing potential can be detected in real time using HP-MR. In these studies we extended these initial experiments to demonstrate that HP-MR can detect parallel and opposing changes in tumor reactive oxygen species (ROS) levels following irradiation. Using the ATC xenograft mouse model we were able to measure acute (2hr) changes in tumor reducing potential following irradiation compared to control tumor (p=0.004). Furthermore, HP-MR allowed us to identify areas of ATC tumors which display enhanced reducing potential, potentially driving ATC radio-resistance. Conclusion: Utilization of HP-MR metabolic imaging has allowed us to further develop our preclinical model of ATC and improve our ability to develop novel translational applications. Specifically, we believe HP-MR can improve the ability to monitor loco-regional tumor growth and invasion, as well as the development of pulmonary metastases. Furthermore, the development of a quantifiable imaging-based biomarker of radiation effect may permit adaptive IR plans based upon tumor response that would optimize disease treatment and improve clinical outcomes. Citation Format: Vlad Sandulache, Yunyun Chen, Jaehyuk Lee, Marc Ramirez, Heath Skinner, Laurence Court, Jim Bankson, Stephen Lai. Using magnetic resonance and hyperpolarized tracers to monitor solid tumor progression, metastasis, and response to treatment. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B07.