MRS of the Prostate
John Kurhanewicz1
1UCSF, United States

Synopsis

Increasing evidence points to prostate cancer being a disease linked to abnormal metabolism, and in this lecture metabolic shifts associated with the presence and progression of prostate cancer and it’s response/resistance to treatment will be described. The quantitative pre-clinical MRS based metabolic and correlative biology studies used to identify biomarkers and the use of these biomarkers in in vivo 1H and HP 13C magnetic resonance spectroscopic imaging studies of patients will be discussed. The need for studies comparing MRSI approaches with current imaging modalities such as multiparametric 1H MRI for localized and PET for metastatic cancer will also be discussed.

TARGET AUDIENCE

This talk is targeted for scientists and clinicians who are interested in using 1H and hyperpolarized (HP) 13C MRS techniques for assessing prostate cancer (PCa) aggressiveness and response/resistance to therapy.

OUTCOME/OBJECTIVES

The participants in this educational session will understand the current metabolic biomarkers of PCa and their mechanistic underpinnings as well the 1H and HP 13C magnetic resonance spectroscopic imaging (MRSI) techniques being used in combination with multiparametric (anatomic, diffusion and perfusion) 1H MRI to select and monitor treatment of PCa.

PURPOSE

The purpose of this educational session is to understand how 1H and HP 13C MRS can be used to address two important clinical questions for PCa patients. 1) Identification of indolent versus aggressive disease at biopsy diagnosis for individualized therapeutic selection. 2) The determination of therapeutic response and development of therapeutic resistance for selection of new therapeutic approaches at an earlier more effective time point.

METHODS

The identification of metabolic biomarkers of PCa aggressiveness and therapeutic response was accomplished through a combination of quantitative MRS based metabolic studies including: 1) Determination of steady state metabolite concentrations using 1H high resolution-magic angle spinning (HR-MAS) 1H spectroscopy of snap-frozen patient biopsies and MRS of tissue extracts. 2) Determination of metabolic fluxes from 13C-decoupled and undecoupled 1H water presaturation, 1H-13C HSQ, and 1H-1H TOCSY MRS studies of [3-13C]pyruvate, [U-13C]glucose and [U-13C]glutamine labeled surgical tissues and PDX model tissues in 2D culture, and HP 13C NMR studies of PCa tissues maintained in an NMR-compatible three-dimensional (3D) tissue culture bioreactor. Prior to patient studies, HP 13C probes identified based on the pre-clinical metabolic studies were validated in GEM and PDX models and correlated with pathologic, IHC staining for hypoxia, proliferation and apoptosis, mRNA expression, protein IHC and activity analysis of key metabolic enzymes and transporters. Hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and frequency specific imaging techniques were also optimized in pre-clinical murine studies and combined with 1H MRSI and multiparametric (anatomic, diffusion and perfusion) 1H MRI in clinical trials of patients prior to surgery and before and after treatment.

DISCUSSION

Increasing evidence points to PCa being a disease strongly linked to abnormal metabolism, and several important metabolic shifts have been associated with the presence and progression of prostate cancer and it’s response to treatment (1,2). The metabolic phenotype of PCa includes increases in phospholipid metabolism, reduced citrate production and increased tricarboxylic cycle (TCA) metabolism, decreased polyamine metabolism, increased aerobic glycolysis and glutaminolysis and increased reducing capacity relative to benign prostate tissue (1,2). More importantly, the magnitude of the metabolic changes in PCa has correlated with pathologic grade thereby providing a read-out on PCa aggressiveness as well as significant changes with therapeutic response (1-5). Specifically for in vivo 1H MRSI, a grade dependent increase in steady state tissue concentrations of choline and ethanolamine phospholipid metabolites and decrease in citrate have been observed and effective treatment has been associated with a loss of choline/ethanolamine metabolites (1). Initial pre-clinical and patient hyperpolarized 13C MRSI studies of PCa have focused on using [1-13C]pyruvate to investigate changes in glycolysis, the conversion of [1-13C]pyruvate to [1-13C]lactate catalyzed by lactate dehydrogenase (LDH). Specifically, both pre-clinical and clinical studies have demonstrated a grade dependent increase in HP [1-13C]lactate with cancer grade/aggressiveness (2-4) and a loss of HP [1-13C]lactate after effective therapy (2,5). HP probes that provide insight into other metabolic pathways, such as [2-13C]pyruvate for assessing TCA metabolism and [5-13C]glutamate for assessing glutaminolysis have been investigated pre-clinically and clinical translation of these probes is in progress (2).

CONCLUSION

The question concerning the relevance of 1H and HP 13C MRS to clinical practice is whether these MRS approaches provide actionable clinical information impacting patient care that is inaccessible by other methods. The potential of 1H and HP 13C MRSI in addressing PCa aggressiveness and therapeutic response, two unmet clinical needs, have been presented in this lecture. Future studies will require comparison of 1H and HP 13C MRSI approaches with current state-of-the-art imaging modalities such as multiparametric 1H MRI for localized prostate cancer and with current HP 13C MRSI studies expanding to metastatic sites within the body (2,6), the comparison of HP 13C MRSI with currently used PET probes.

Acknowledgements

Contributing authors will be acknowledged on the slides containing their research.

References

  1. Kurhanewicz J, Vigneron D. MRS in Prostate Cancer in Handbook of Magnetic Resonance Spectroscopy In Vivo: MR Theory, Practice and Applications, Bottomley, P.A. and Griffiths, J.R. (eds). John Wiley & Sons Ltd, Chichester, UK, pp 997-1023. 20162.
  2. Kurhanewicz, J., Vigneron, D. B., Ardenkjaer-Larsen, J. H., et. al., Hyperpolarized (13)C MRI: Path to Clinical Translation in Oncology. Neoplasia 2019 Jan;21(1):1-16., PMCID:6260457.3.
  3. Bok, R., Lee, J. Sriram, R. Keshari, K., et. al. The Role of Lactate Metabolism in Prostate Cancer Progression and Metastases Revealed by Dual-Agent Hyperpolarized (13)C MRSI. Cancers 11(2), (Feb 22, 2019).4.
  4. Granlund, K. L.; Tee, S. S.; Vargas, H. A.; et. al.. Hyperpolarized MRI of Human Prostate Cancer Reveals Increased Lactate with Tumor Grade Driven by Monocarboxylate Transporter 1. Cell Metabolism 2020, 31, 105–114.e3.5.
  5. 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, Sept, 2017;72(6)1028-1029. PMCID: PMC57232066.
  6. H.-Y. Chen, R. Aggarwal, R. A. Bok, M. A., et. al., Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study. Prostate Cancer Prostatic Dis, (2019) doi:10.1038/s41391-019-0180-z.
Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)