Abstract 210: In vivo metabolic imaging to differentiate aggressive versus indolent prostate cancer
Authors: Zacharias Millward Niki , McCullough Christopher , Lee Youngbok , Hu Jingzhe , Dutta Prasanta , Piwnica-Worms David , Bhattacharya Pratip 
Published: August 2015

Abstract
Purpose: Many prostate cancers (PCa) detected by screening are indolent (will not leave the prostate) however, 90% of patients will receive immediate treatment such as surgery or radiation therapy. There is a pressing need in the clinic for determining the aggressiveness of PCa that allows the whole prostate to be examined and is directly correlated to the metastatic behavior of the tumor. We are using a multi-prong approach to understand the metabolic changes that occur in the progression of PCa. (1) We are metabolic profiling tumor and normal prostate tissue. (2) We are metabolic profiling both the intracellular and secretion/consumption of metabolites of four human prostate cancer cell lines with different aggressiveness profiles: RWPE-1 (non-tumorigenic, considered benign), RWPE-2 (non-metastatic), PC3 (aggressive, castration resistant), most aggressive cell line PC3M (castration resistant). (3) We are following the progression of PCa with hyperpolarized magnetic resonance (MR) agents in PCa animal models. Hyperpolarization allows for over &gt;10,000 fold sensitivity enhancement using conventional MRI and MRS. The polarization (signal enhancement) can be retained on the metabolites of the hyperpolarized molecule. Hyperpolarization allows for in vivo real time metabolic profiling. Results: Based on our metabolic profiling of PCa tissue and cell culture, we observe significant differences in uptake of glutamine and the amount of intracellular glutamine, differences in phosphocholine and glycerophosphocholine, and differences in intracellular succinate levels between aggressive versus non-aggressive cell lines and in PCa tissue versus normal prostate tissue. In addition, in our hands we see no significant difference in the glycolytic rate (production of lactate) between the indolent and aggressive PCa cell lines in culture. Using dynamic nuclear polarization, we are designing new in vivo methods for interrogating metabolic pathways. Using our chemical reaction-induced multi-molecular polarization (CRIMP) technique, we can fully transfer the high polarization levels of pyruvate in an irreversible reaction to 1-13C acetate and 13C-carbon dioxide without substantial signal loses. Because hyperpolarized carbon dioxide nearly instantly equilibrates with bicarbonate in the aqueous environment, the pH of the media can be simply calculated from the signal intensity ratio of the two compounds using the Henderson Hasselbalch equation. Discussion: As an alternative to hyperpolarized pyruvate for analysis of the aggressiveness of prostate cancer, compounds that more comprehensively interrogate glutaminolysis, choline metabolism, and the Krebs cycle in combination may provide better metabolic imaging information. Using the CRIMP technique and single component hyperpolarization of 15N-choline, we are currently using MR to metabolically image PCa animal models.
Citation Format: Niki Zacharias Millward, Christopher McCullough, Youngbok Lee, Jingzhe Hu, Prasanta Dutta, David Piwnica-Worms, Pratip Bhattacharya. In vivo metabolic imaging to differentiate aggressive versus indolent prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 210. doi:10.1158/1538-7445.AM2015-210