a) Relationship between tumor pO2 and metabolic profile (glycolysis): It is well known that tumors have low pO2 and also display the Warburg phenotype where they have efficient glycolysis even in presence of oxygen. Since our lab is uniquely capable of co-registering the glycolytic maps of tumor with maps of pO2, we sequentially imaged tumors in mice for pO2 and conversion kinetics of hyperpolarized [1-13C] pyruvate to [1-13C] to represent glycolysis. We have successfully conducted such experiments in MiaPaca2 pancreatic carcinoma xenograft to obtain a statistically reliable relationship between tumor pO2 and glycolytic activity. We found that the glycolytic activity is inversely related to tumor pO2. We have found this pattern across the tumor cell lines in three different pancreatic carcinoma xenografts, Su8686, MiaPaca2, and Hs766t. ThepO2 in these tumor xenografts followed Su8686MiaPaca2Hs766t where as the glycolytic activity, monitored by the conversion of hyperpolarized [1-13C] pyruvate to [1-13C] followed H2766tMiaPaca2Su8686. b) Hyperpolarized MRI for treatment response with anticancer drugs: Since metabolic/physiological changes manifest early in treatment phase than volumetric changes, we examined of the conversion rates of hyperpolarized [1-13C] pyruvate to [1-13C] reflects treatment efficacy using VEGFR inhibitors Sunitinib, and Vandetanib and the proteosomal activity inhibitor Marizomib. In all these cases we have found changes in the kinetics of conversion of pyruvate to lactate to decrease even 1 day after treatment validating the use of this approach clinically. Further with Sunitinib, we have been able to identify the temporal window of vascular re-normalization making this useful to schedule combination treatments with anti-angiogenic drug treatments. c) Novel tracers for metabolic imaging. We have been using pyruvate exclusively for metabolic MRI. While this tracer is giving valuable insights into the metabolic profile of tumors, additional tracers are critical in understanding the citric acid cycle. Towards this goal, we have started synthesis of tracers such as glucose, diethylsuccinate, acetate, and also the ROS indicator, Dimethyl pyrroline 1-Oxide (DMPO). We have successfully tested the capability of diethylsuccinate in in vivo studies to report on various metabolic reactions in the tumor. We also succeeded in identifying a carbon atom in DMPO for polarization and developed methods to polarize it to necessary levels. This experiment was done in DMPO with naturally abundant 13C (0.1%). With the success in detecting signals after hyperpolarization, we have embarked on synthesis of 13C labeled DMPO along with 1-Glucose.
|Kishimoto, Shun; Bernardo, Marcelino; Saito, Keita et al. (2015) Evaluation of oxygen dependence on in vitro and in vivo cytotoxicity of photoimmunotherapy using IR-700-antibody conjugates. Free Radic Biol Med 85:24-32|
|Matsumoto, Shingo; Saito, Keita; Yasui, Hironobu et al. (2013) EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate. Magn Reson Med 69:1443-50|
|Matsumoto, Shingo; Batra, Sonny; Saito, Keita et al. (2011) Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res 71:6350-9|
|Day, Sam E; Kettunen, Mikko I; Cherukuri, Murali Krishna et al. (2011) Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1- 13C]pyruvate and 13C magnetic resonance spectroscopic imaging. Magn Reson Med 65:557-63|