Hyperpolarized (13)C MRSI for Therapeutic Response Monitoring of Prostate Cancer to Radiotherapy

Abstract

Purpose/Objective(s)

Radiotherapy is a widely used mode of treatment for prostate cancer. As patients respond to radiation differently, early detection of therapeutic response is necessary to choose the most appropriate treatment plan. Taking the advantage of cancer specific aerobic glycolysis, known as the ‘Warberg effect’, metabolic imaging with hyperpolarized ¹³C-labeled pyruvate (pyr) has demonstrated potential of early detecting prostate cancer; a potentially better alternative to conventional therapeutic response monitoring that takes months to become apparent. In this technique, the transient fate of pyr and its downstream metabolites lactate (lac), alanine, and bicarbonate is measured with ¹³C Magnetic Resonance Spectroscopy Imaging (MRSI) following an injection of hyperpolarized pyr. Our aim is to investigate the efficacy of this technique to monitor the therapeutic response of prostate cancer to radiotherapy.

Materials/Methods

A cross-sectional study was designed to assess metabolic response of prostate cancer to radiotherapy in transgenic mouse model of prostatic adenocarcinoma (TRAMP), a model that closely resembles human prostate cancer. The tumor volume of three experimental groups, containing ≥4 mice in each for statistical significance, was followed biweekly by T2-weighted MRI at 7 T. When tumor reached ∼1.5 cm, Group-1 was subjected to ¹³C MRSI at 3T to set the baseline. Group-2 with the same lesion size as Group-1 was given radiation (∼20 Gy at 200 kVp) before ¹³C MRSI. Group-3, which received no treatment, was subjected to ¹³C MRSI at the same postirradiation as Group-2. Histopathology was performed on all mice after ¹³C MRSI for tumor grading. The hyperpolarization was achieved by dynamic nuclear polarization, i.e., irradiating a mixture of [1-¹³C]pyruvic acid, trityl radicals, and Gd²⁺, at 1.4 K and 3.3 T field with 94 GHz microwaves. Before the injection into the mouse via jugular vein catheter, the polarized substrate was quickly dissolved in Tris/EDTA and NaOH at 37°C, yielding 80 mM pyr solution at natural pH. A fast 3D dynamic spectroscopy sequence was employed to acquire ¹³C spectra of the prostate following the injection. Metabolic maps of each metabolite were obtained by peak integration. The average concentration of metabolites was measured in regions of interest using metabolic maps assisted with MRI anatomical reference images.

Results

Conversion of pyr to lac is often characterized by lac/pyr ratio. This ratio was found to be highest in Group-3.

Conclusions

Our initial experience suggests capability of using metabolic changes measured by ¹³C MRSI for detecting therapeutic response of prostate cancer to radiation in TRAMP mice. Further investigations are underway for assessing the best metabolic metrics correlating with histopathology of prostate.