Abstract 2852: Monitoring the impact on metabolic fluxin vivoof a newly developed LDH inhibitor using hyperpolarized 13C magnetic resonance spectroscopic imaging
Authors: Nobu Oshima, Shun Kishimoto, Kristin Beebe, Keita Saito, Kazutoshi Yamamoto, Jeffery Brender, Anastasia Sowers, Ganesha Rai, Bryan T. Mott, David J. Maloney, James B. Mitchell, Murali K. Cherukuri, Leonard M. Neckers
Journal: Cancer Research (2017)

Abstract [aim] Increased lactate production is a feature of many neoplasms, and Lactate Dehydrogenase A (LDH-A) plays a key role in conversion of pyruvate to lactate. LDHA inhibition, therefore, is considered to be a promising approach toward developing a new therapeutic strategy for cancer treatment focused on targeting cancer metabolism. Non-invasive imaging approaches able to monitor metabolic fluxes in vivo will be useful for this purpose. Hyperpolarized 13C Magnetic Resonance Imaging (MRI) has been well known as a valuable technology to investigate metabolic processes in tumor xenografts, allowing us to perform dynamic 13C-metabolic flux analysis in vivo. Use of [1-13C]pyruvate with this technology provides the ability to monitor LDHA activity in real time through dynamic observation of conversion of [1-13C]pyruvate to [1-13C]lactate. This study aimed to monitor drug efficacy of a newly developed LDH inhibitor (LDHI, obtained from National Cancer Institute Experimental Therapeutics Program, NExT) in a xenograft tumor model using 13C MRI technology with hyperpolarized 13C-labeled pyruvate. [Results] Hyperpolarized [1-13C]pyruvate MR studies were performed before and after LDHI administration to assess the impact on metabolic flux in vivo. Using hyperpolarized [1-13C]pyruvate MR Spectroscopy (MRS), we found that lactate production was significantly suppressed by LDHI administration in MiaPaca (a glycolytic pancreatic cancer cell line) tumors, as was the [1-13C]lactate to [1-13C]pyruvate ratio ([1-13C]-Lac/Pyr), which was calculated from the areas under the curves (AUC) using time-intensity data. This ratio decreased from 1.08 to 0.128 (88.1% decrease) 30 minutes after intravenous administration of the LDHI. In addition, hyperpolarized [1-13C]pyruvate MRS revealed that LDHI significantly suppressed lactate production in a dose dependent manner. Furthermore, Chemical Shift Imaging with 13C MRI demonstrated that the [1-13C]lactate signal in each voxel clearly decreased, compared to that before LDHI administration. The sum of [1-13C]lactate signals in the tumor region decreased after LDHI administration, resulting in a significant decrease in the tumor-specific [1-13C] Lac/Pyr ratio (1.463±0.31 before LDHI to 0.134±0.036 30 minutes after LDHI administration, a 90.67±2.56% decrease, n=3, p&amp;lt;0.01). [Conclusions] These results indicate that hyperpolarized 13C-MRI is a useful method to evaluate on-target efficacy of novel LDH inhibitors in vivo, and this technique can be used to determine optimum dose and exposure time of the LDHI in the tumor region. The current method can be of great value in providing an in vivo pharmacodynamic biomarker for this novel anti-cancer therapeutic targeting deregulated tumor metabolism. Citation Format: Nobu Oshima, Shun Kishimoto, Kristin Beebe, Keita Saito, Kazutoshi Yamamoto, Jeffery Brender, Anastasia Sowers, Ganesha Rai, Bryan T. Mott, David J. Maloney, James B. Mitchell, Murali K. Cherukuri, Leonard M. Neckers. Monitoring the impact on metabolic flux in vivo of a newly developed LDH inhibitor using hyperpolarized 13C magnetic resonance spectroscopic imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2852. doi:10.1158/1538-7445.AM2017-2852