Metabolic Imaging in Prostate Cancer

Androgen-deprivation therapy is an effective treatment for prostate cancer, however after 2 to 3 years the lethal phenotype, castrate-resistant prostate cancer (CRPC), emerges which is incurable. The therapy induced progression of prostate cancer to CRPC leads to two distinct tumors subtypes based on clinicopathologic and genomic characterizations. One tumor subtype reactivates androgen receptor (AR) signaling by AR amplification, promiscuous ligand binding through AR point mutations, intratumoral androgen biosynthesis and/or generation of splice variants of the AR gene. The second subtype, aggressive variant PCa (AVPC), is phenotypically similar to small cell prostate cancer with loss of AR expression, gain of neuroendocrine or pro-neural marker expression, sensitivity to chemotherapy and combined alterations of PTEN, TP53 and RB1 tumor suppressor proteins. During progression to CPRC, serum PSA levels and bone scans provide valuable prognostic information to the clinicians but they do not expose the altered tumor biology that helps to direct personalized precision therapy. Identifying these two groups is critical in optimizing therapy to improve patient outcome. In a collaboration between the departments of Genitourinary Medical Oncology and Cancer Systems Imaging at the University of Texas, MD Anderson Cancer Center, we integrated quantitative mass spectrometry and nuclear magnetic resonance (NMR) analytical methods with hyperpolarized ¹³C magnetic resonance imaging to define unique metabolome alterations in preclinical models of AR positive CRPC and AR negative AVPC¹.

Our goal in this research project was to identify unique CRPC tumor bioenergy metabolome profiles and track metabolic pathway biomarkers in vivo in real time. To date, the most well-characterized hyperpolarized ¹³C compound is pyruvate. The utility of hyperpolarized pyruvate in metabolic imaging has been explored extensively, and the first study in humans was concluded at the University of California, San Francisco in 2013². Hyperpolarized pyruvate can be used to follow lactate dehydrogenase (LDH) metabolism of pyruvate to lactate. The rate of hyperpolarized lactate production has been revealed as a metabolic biomarker for cancer in multiple preclinical animal studies³. In addition to imaging tumor LDH ¹³C-pyruvate to lactate transition, we monitored bioenergy intermediates and testosterone levels using NMR and mass spectrometry. These analytical instruments allow quantitation and validation of target metabolites, such as lactate and Krebs Cycle metabolites, in the CRPC tumor subtypes. The combination of known genomic alterations with metabolomics data support a multicomponent biomarker panel to distinguish these two preclinical CRPC subtypes.

Moreover, metabolic imaging using hyperpolarized ¹³C-pyruvate may expand to other minimally invasive applications ranging from detection of early stage cancerous tissues, determination of androgen deprivation therapy efficacy in real time, as well as establishing tumor margins after surgical treatment. Real-time metabolic resonance imaging may establish a new paradigm wherein the local status of tumor metabolism is interrogated on the time scale of seconds to minutes with unprecedented sensitivity of metabolic resonance.

The real-time in vivo ¹³C hyperpolarization of CRPC or prostate cancer will also complement non-invasive liquid biopsies from patient blood or urine. Patient serum or plasma is an optimum source for biomolecules / biomarkers originating directly from tumor cells and provide insight into the disease state. Prostate tumors shed lipid, RNA, DNA, exosomes and intact tumor cells into blood. Circulating tumor DNA provides consistent information on genomic alterations that occur in the original tumor and circulating tumor cells provide downstream sequencing information from the tumor to help determine the functional AR axis during prostate cancer progression. We believe that in vivo metabolomics is the new frontier in prostate cancer characterization; with the combined knowledge of genomics and proteomics, a complete understanding of tumor progression might be achieved. An accessible goal for translational research scientists wishing to impact prostate cancer therapy is to: (a) identify disease biomarkers during therapy-induced resistance to optimize treatment, and (b) to do this safely, efficiently and non-invasively with ever increasing specificity and sensitivity. Are we at the threshold of high definition metabolic biomarker and targeted molecular imaging in patients using novel MR techniques? We are hopeful that our multidisciplinary collaborative efforts here at MD Anderson Cancer Center will lead the way to breakthroughs in real-time oncologic imaging in magnetic resonance in the near future!

References:
1. Zacharias NZ, Lee J, Ramachandran S et al (2018) Androgen receptor signaling in castration resistant prostate cancer tumor alters hyperpolarized pyruvate to lactate conversion and lactate levels in vivo. Molecular Imaging and Biology 14: 1-9.
2. Nelson SJ, Kurhanewicz J, Vigneron DB et al (2013) Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate. Science Translational Med 5:198ra108
3. Golman K, Zandt RI, Lerche M et al (2006) Metabolic imaging by hyperpolarized ¹³C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Research 66:10855–10860

Written by:
Mark A Titus¹, Daniel Frigo^1,2, Eleni Efstathiou¹, Christopher J Logothetis¹, David Piwnica-Worms², Pratip Bhattacharya²
1. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
2. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX

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