Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology

Abstract

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) ¹³C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized ¹³C MRI in 2011, preclinical studies involving [1-¹³C]pyruvate as well a number of other ¹³C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-¹³C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP ¹³C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.

Figure 1

Schematic showing the required components for HP ¹³C MRI clinical translation. Thirty-two-channel head coil.

Figure 2

Images are from a representative patient with a current PSA of 3.6 ng/ml, who had biopsy-proven prostate cancer in the left apex (Gleason grade 3 + 4) and received the highest dose of hyperpolarized [1-¹³C]pyruvate (0.43 ml/kg). (A) A focus of mild hypointensity can be seen on the T₂-weighted image, which was consistent with the biopsy findings. (B to D) 2D localized dynamic hyperpolarized [1-¹³C]pyruvate and [1-¹³C]lactate from spectral data that were acquired every 5 seconds from voxels overlapping the contralateral region of prostate (turquoise), a region of prostate cancer (yellow), and a vessel outside the prostate (green). The dynamic data were fit to provide k_PL as described previously. Figure taken from Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PEZ, Harzstark AL, Ferrone M, et al. Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate. Science Translational Medicine 2013;5:198ra108-198ra108.

Figure 3

Representative axial T₂-weighted anatomic image and corresponding water apparent diffusion coefficient (ADC) image and T₂W image with an overlaid pyruvate-to-lactate metabolic flux (k_PL) image and corresponding HP ¹³C spectral array for a 52-year-old prostate cancer patient with extensive high-grade prostate cancer (A) before therapy and (B) 6 weeks after initiation of androgen ablation and chemotherapy. Before treatment, the region of prostate cancer can be clearly seen (red arrows) as a reduction in signal on the T₂W and ADC images, and increased HP lactate and associated k_PL on. Pretreatment, HP [1-¹³C]pyruvate CS-EPSI demonstrated a large region of high HP Lac/Pyr ratio, resulting in a high k_PL, which is consistent with region of decreased T₂ MRI signal and water ADC associated with biopsy-proven Gleason 4 + 5 prostate cancer. At 6 weeks after initiation of androgen deprivation therapy, repeat HP ¹³C MRI demonstrated nearly complete abrogation of elevated HP lactate peaks and associated near-complete diminution of intratumoral k_PL values on dynamic imaging (k_PL max 0.025 s⁻¹ at baseline and 0.007 s⁻¹ on follow-up). Notably, there were negligible change in size of tumor on T₂-weighted MRI and only a modest change on ADC imaging, supporting the ability of HP ¹³C MRI to detect early metabolic responses before such a response can be ascertained using standard radiographic criteria. Concordant with these findings, the patient subsequently achieved a marked clinical response, with an undetectable serum PSA nadir at 6 months after ADT initiation. Figure taken from Aggarwal, R., Vigneron, D.B., and Kurhanewicz, J. Hyperpolarized [1-¹³C] Pyruvate Magnetic Resonance Imaging Detects an Early Metabolic Response to Androgen Ablation Therapy in Prostate Cancer, Eur Uro, July 23, 2017;72(6)1028-1029. PMCID:5723206.