Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion.

New magnetic resonance (MR) molecular imaging techniques offer the potential for noninvasive, simultaneous quantification of metabolic and perfusion parameters in tumors. This study applied a three-dimensional dynamic dual-agent hyperpolarized 13C magnetic resonance spectroscopic imaging approach with 13C-pyruvate and 13C-urea to investigate differences in perfusion and metabolism between low- and high-grade tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) transgenic mouse model of prostate cancer. Dynamic MR data were corrected for T1 relaxation and RF excitation and modeled to provide quantitative measures of pyruvate to lactate flux (kPL ) and urea perfusion (urea AUC) that correlated with TRAMP tumor histologic grade. kPL values were relatively higher for high-grade TRAMP tumors. The increase in kPL flux correlated significantly with higher lactate dehydrogenase activity and mRNA expression of Ldha, Mct1, and Mct4 as well as with more proliferative disease. There was a significant reduction in perfusion in high-grade tumors that associated with increased hypoxia and mRNA expression of Hif1α and Vegf and increased ktrans , attributed to increased blood vessel permeability. In 90% of the high-grade TRAMP tumors, a mismatch in perfusion and metabolism measurements was observed, with low perfusion being associated with increased kPL This perfusion-metabolism mismatch was also associated with metastasis. The molecular imaging approach we developed could be translated to investigate these imaging biomarkers for their diagnostic and prognostic power in future prostate cancer clinical trials. Cancer Res; 77(12); 3207-16. ©2017 AACR.

[1]  John M Pauly,et al.  Double spin-echo sequence for rapid spectroscopic imaging of hyperpolarized 13C. , 2007, Journal of magnetic resonance.

[2]  John Kurhanewicz,et al.  Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. , 2011, Neoplasia.

[3]  J. Kurhanewicz,et al.  Endorectal MRI and MR spectroscopic imaging of prostate cancer: Developing selection criteria for MR‐guided focal therapy , 2014, Journal of magnetic resonance imaging : JMRI.

[4]  R. Deberardinis,et al.  Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? , 2012, Cell.

[5]  E. T. Gawlinski,et al.  Acid-mediated tumor invasion: a multidisciplinary study. , 2006, Cancer research.

[6]  Shingo Matsumoto,et al.  Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. , 2011, Cancer research.

[7]  John Kurhanewicz,et al.  Metabolic Reprogramming and Validation of Hyperpolarized 13C Lactate as a Prostate Cancer Biomarker Using a Human Prostate Tissue Slice Culture Bioreactor , 2013, The Prostate.

[8]  Hessel Wijkstra,et al.  The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel , 2014, BJU international.

[9]  J. Berwick,et al.  Kinetic modeling of hyperpolarized 13C pyruvate metabolism in tumors using a measured arterial input function , 2013, Magnetic resonance in medicine.

[10]  M. Knopp,et al.  Estimating kinetic parameters from dynamic contrast‐enhanced t1‐weighted MRI of a diffusable tracer: Standardized quantities and symbols , 1999, Journal of magnetic resonance imaging : JMRI.

[11]  S. Bröer,et al.  The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. , 2000 .

[12]  Robert J Gillies,et al.  Acidity generated by the tumor microenvironment drives local invasion. , 2013, Cancer research.

[13]  C. Dang,et al.  Oncogenic alterations of metabolism and the Warburg effect , 2005 .

[14]  C. Ménard,et al.  Tumor Hypoxia Predicts Biochemical Failure following Radiotherapy for Clinically Localized Prostate Cancer , 2012, Clinical Cancer Research.

[15]  H. Coller.  Is cancer a metabolic disease? , 2014, The American journal of pathology.

[16]  A. Lardner.  The effects of extracellular pH on immune function , 2001, Journal of leukocyte biology.

[17]  Bing Zhang,et al.  [Expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor in prostate cancer and its significance]. , 2006, Zhonghua nan ke xue = National journal of andrology.

[18]  John Kurhanewicz,et al.  Imaging of blood flow using hyperpolarized [13C]Urea in preclinical cancer models , 2011, Journal of magnetic resonance imaging : JMRI.

[19]  M. Giger,et al.  Quantitative analysis of multiparametric prostate MR images: differentiation between prostate cancer and normal tissue and correlation with Gleason score--a computer-aided diagnosis development study. , 2013, Radiology.

[20]  J. Pouysségur,et al.  Disrupting proton dynamics and energy metabolism for cancer therapy , 2013, Nature Reviews Cancer.

[21]  O. Feron,et al.  Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[22]  M. Lustig,et al.  Fast dynamic 3D MR spectroscopic imaging with compressed sensing and multiband excitation pulses for hyperpolarized 13C studies , 2011, Magnetic resonance in medicine.

[23]  J. Kurhanewicz,et al.  Human prostate cancer ZIP1/zinc/citrate genetic/metabolic relationship in the TRAMP prostate cancer animal model , 2011, Cancer biology & therapy.

[24]  Michael Lustig,et al.  3D compressed sensing for highly accelerated hyperpolarized 13C MRSI with in vivo applications to transgenic mouse models of cancer , 2010, Magnetic resonance in medicine.

[25]  C. Nanni,et al.  Positron-emission tomography in imaging and staging prostate cancer. , 2008, Cancer biomarkers : section A of Disease markers.

[26]  Steven J. M. Jones,et al.  A multi-institutional evaluation of active surveillance for low risk prostate cancer. , 2013, The Journal of urology.

[27]  Jason C. Crane,et al.  SIVIC: Open-Source, Standards-Based Software for DICOM MR Spectroscopy Workflows , 2013, Int. J. Biomed. Imaging.

[28]  Albert P. Chen,et al.  Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. , 2008, Cancer research.

[29]  A. Haase,et al.  Apparent rate constant mapping using hyperpolarized [1–13C]pyruvate , 2014, NMR in biomedicine.

[30]  B. Foster,et al.  Pathologic progression of autochthonous prostate cancer in the TRAMP model , 1999, Prostate Cancer and Prostatic Diseases.

[31]  John Kurhanewicz,et al.  Hyperpolarized 13C MR for Molecular Imaging of Prostate Cancer , 2014, The Journal of Nuclear Medicine.

[32]  Adam B Kerr,et al.  Quantitative measurement of cancer metabolism using stimulated echo hyperpolarized carbon‐13 MRS , 2014, Magnetic resonance in medicine.

[33]  J. Kurhanewicz,et al.  Evaluation of lactate and alanine as metabolic biomarkers of prostate cancer using 1H HR‐MAS spectroscopy of biopsy tissues , 2008, Magnetic resonance in medicine.

[34]  A. Oto,et al.  Diffusion-weighted and dynamic contrast-enhanced MRI of prostate cancer: correlation of quantitative MR parameters with Gleason score and tumor angiogenesis. , 2011, AJR. American journal of roentgenology.

[35]  P. Porporato,et al.  Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. , 2012, Current pharmaceutical design.

[36]  Robert B Livingston,et al.  Blood flow and metabolism in locally advanced breast cancer: relationship to response to therapy. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[37]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[38]  Daniel B Vigneron,et al.  Kinetic and perfusion modeling of hyperpolarized (13)C pyruvate and urea in cancer with arbitrary RF flip angles. , 2014, Quantitative imaging in medicine and surgery.

[39]  J Kurhanewicz,et al.  Dynamic nuclear polarization of biocompatible (13)C-enriched carbonates for in vivo pH imaging. , 2016, Chemical communications.

[40]  D. Mankoff,et al.  Blood Flow-Metabolism Mismatch: Good for the Tumor, Bad for the Patient , 2009, Clinical Cancer Research.

[41]  R K Jain,et al.  Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. , 2001, Cancer research.

[42]  Franziska Hirschhaeuser,et al.  Lactate: a metabolic key player in cancer. , 2011, Cancer research.

[43]  John Kurhanewicz,et al.  Multi-compound polarization by DNP allows simultaneous assessment of multiple enzymatic activities in vivo. , 2010, Journal of magnetic resonance.

[44]  P. Larson,et al.  Metabolic Imaging of Patients with Prostate Cancer Using Hyperpolarized [1-13C]Pyruvate , 2013, Science Translational Medicine.

[45]  L. Holmberg,et al.  Serum lactate dehydrogenase and survival following cancer diagnosis , 2015, British Journal of Cancer.

[46]  S. Barni,et al.  Prognostic role of lactate dehydrogenase in solid tumors: A systematic review and meta-analysis of 76 studies , 2015, Acta oncologica.

[47]  F. Saad,et al.  Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. , 2015, The Lancet. Oncology.

[48]  Marc S Ramirez,et al.  Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors. , 2015, Cancer research.

[49]  T. DeGrado,et al.  ORIGINAL ARTICLE: Pilot comparison of 18F‐fluorocholine and 18F‐fluorodeoxyglucose PET/CT with conventional imaging in prostate cancer , 2010, Journal of medical imaging and radiation oncology.