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!
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
Mark A Titus1, Daniel Frigo1,2, 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
Read the Abstract