Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study

Abstract

Background: Hyperpolarized (HP) ¹³C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP ¹³C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.

Methods: Six patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized ¹³C-pyruvate, where pyruvate-to-lactate conversion rate (k_PL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.

Results: We observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean k_PL value of 0.020 ± 0.006 (s^-1) and 0.026 ± 0.000 (s^-1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high k_PL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of k_PL from 0.026 at baseline to 0.015 (s^-1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).

Conclusions: HP ¹³C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative k_PL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP ¹³C-pyruvate MRI in the setting of advanced prostate cancer.

Fig. 1

An illustration of LDH-mediated aerobic glycolysis and relevant metabolic pathways

Fig. 2

a Patient 1 (75 years old) was diagnosed with metastatic castration-resistant prostate cancer with several large osteoblastic lesions throughout the left hemipelvis and involving left femur. CT identified a relatively osteolytic lesion in left ilium (Green arrows), measuring 9.9 × 4.1 cm. The lesion was infiltrative, causing destruction of the bone cortex and extension into the surrounding soft tissues. T1-weighted (T₁w) spoiled gradient-echo MRI was used to target the same lesion observed on CT for the HP ¹³C MR acquisition. Regions of high pyruvate-to-lactate conversion rate (k_PL) correlated with the osseous lesion on CT and hypointensity on T₁w MRI. k_PL was estimated 0.013 (s⁻¹). b The paired bone biopsy demonstrated discrete regions of adenocarcinoma and treatment-emergent small cell neuroendocrine differentiation

Fig. 3

Patient 2 (57 years old) was diagnosed with CRPC that metastasized to liver. The patient was previously treated with enzalutamide and an investigational agent (BET inhibitor, phase I) with clinical progression. Chemotherapy of carboplatin and docetaxel started ~1 month post baseline HP ¹³C scan, and follow-up was 2 months after initiation of therapy. a A decrease in pyruvate-to-lactate conversion rate k_PL was observed from 0.026 to 0.015 (s⁻¹) after 2 months of chemotherapy. Note the increase in pyruvate and lactate at 50–60 s post injection. Most likely this is predominately due to vascular contributions coming from intestines. b Follow-up 2 months after initiation of therapy found a decrease in lesion size (19.3–11.8 mm) indicating therapeutic response based on RECIST criteria. c In addition, serum PSA decreased from 38–13.4 ng/ml also indicating therapeutic response. HA arterial phase, PV portal venous phase