Abstract SY19-03: Translation of hyperpolarized13C imaging to the clinic

A decade after the first demonstration of dissolution-DNP by Ardenkjaer-Larsen et al.(1), metabolic imaging using HP [1- 13 C]pyruvate was accomplished in prostate cancer patients(2). Translation of this technology into patients required the development and optimization of a clinical DNP polarizer, the implementation of multinuclear MR capabilities on clinical MRI scanners, the construction of specialized radio frequency (RF) coils to detect 13 C nuclei, and developing new MR pulse sequences to efficiently capture the signal (2). These steps towards translation will be presented with emphasis on where the translation process stands currently. Additionally, studies involving preclinical prostate cancer models played an important role in establishing the potential clinical value of HP [1- 13 C]pyruvate in prostate cancer. Preclinical studies in prostate cancer models have detected elevated levels of hyperpolarized [1- 13 C]lactate in tumor, with the ratio of [1- 13 C]lactate/[1- 13 C]pyruvate being increased in high-grade tumors and decreased after successful treatment(3). This preclinical data was critical to obtaining the US Food and Drug Administration (FDA) Investigational New Drug (IND) approval for the first human trial and setting the stage for ongoing clinical trials of HP [1- 13 C]pyruvate. The Phase 1 clinical trial evaluated the safety and feasibility of hyperpolarized [1- 13 C]pyruvate as an agent for noninvasively characterizing alterations in tumor metabolism for patients with prostate cancer. Increasing evidence points to prostate cancer being a disease strongly linked to abnormal metabolism, and several important metabolic shifts have been associated with the presence and progression of prostate cancer (4). The median time to delivery of hyperpolarized 13 C pyruvate was 66 s, and uptake was observed about 20 s after injection. No dose-limiting toxicities were observed, and the highest dose (0.43 ml/kg of 230 mM agent) gave the best signal-to-noise ratio for hyperpolarized [1- 13 C]pyruvate. The results were extremely promising in not only confirming the safety of the agent but also showing elevated [1- 13 C]lactate/[1- 13 C]pyruvate in regions of biopsy-proven cancer. There was increased conversion of [1- 13 C]pyruvate to [1- 13 C]lactate in the tumor, with the [1- 13 C]pyruvate reaching a maximum by 18 ± 4 s and the [1- 13 C]lactate reached a maximum at 27 ± 2 s after the start of acquisition, which was 5 s after the end of injection. The timings of maximal signal were similar to those observed in preclinical murine and human tissue slice culture hyperpolarized [1- 13 C]pyruvate studies (4). Overall, the pyruvate to lactate flux (mean ± SD) was 0.045 ± 0.025 s −1 for [1- 13 C]pyruvate to [1- 13 C]lactate in tumor voxels and 0.009 ± 0.003 s −1 for voxels coming from regions that included blood vessels. Although there was sufficient lactate signal to determine a pyruvate to lactate flux for the contralateral normal prostate in this example (0.016 s −1 ), a majority of normal prostate demonstrated hyperpolarized lactate levels that were to low to accurately calculate a pyruvate to lactate flux. Ongoing hyperpolarized [1- 13 C]pyruvate studies in prostate cancer patients are investigating the test-retest reproducibility of [1- 13 C]pyruvate delivery and metabolism, response to androgen deprivation therapy, the development of androgen-independent disease and its response to new 2 nd line therapeutic approaches. The current results of these studies will be presented. Sixteen sites from around the world currently have DNP Polarizers capable of performing patient studies, with a number of new installations planned for the coming year. Additionally, eighteen hyperpolarized patient studies are currently funded involving a total of 864 patients with prostate, brain and breast cancer prior to and after therapy. Most of these trials are focused on the use of HP [1- 13 C]pyruvate, but there are a number of new hyperpolarized 13 C labeled probes that are in the clinical pipeline and these will be summarized in this lecture. References 1. Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH, Servin R, Thaning M, & Golman K Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proc Natl Acad Sci U S A. 2003; 100(18),10158-10163. 2. Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PE, Harzstark AL, Ferrone M, van Criekinge M, Chang JW, Bok R, Park I, Reed G, Carvajal L, Small EJ, Munster P, Weinberg VK, Ardenkjaer-Larsen JH, Chen AP, Hurd RE, Odegardstuen LI, Robb FJ, Tropp J, & Murray JA Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate. Sci Transl Med. 2013; 5(198),198ra108. 3. Sriram R, Kurhanewicz J, & Vigneron D (2014) Hyperpolarized Carbon-13 MRI and MRS Studies. eMagRes. 3(4):311-324. DOI: 10.1002/9780470034590.emrstm1253. 4. Keshari KR, Sriram R, Van Criekinge M, Wilson DM, Wang ZJ, Vigneron DB, Peehl DM, & Kurhanewicz J Metabolic reprogramming and validation of hyperpolarized (13)C lactate as a prostate cancer biomarker using a human prostate tissue slice culture bioreactor. Prostate. 2013; 73(11),1171-1181. Citation Format: John Kurhanewicz. Translation of hyperpolarized 13 C imaging to the clinic. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY19-03.