Distinguishing Closely Related Pancreatic Cancer Subtypes In Vivo by 13C Glucose MRI without Hyperpolarization

Metabolic differences between patients and within the tumor itself can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo have been lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of metabolism, as detected by imaging of uniformly 13C labeled glucose tracers using a newly developed technique using tensor decomposition for noise suppression to bring the signal to a detectable level without hyperpolarization of the tracer. Using this method, cancer subtypes that appeared to exhibit similar metabolic profiles by other techniques that measured steady state metabolism can be distinguished.

[1]  H. Kocher,et al.  Pancreatic Cancer , 2019, Methods in Molecular Biology.

[2]  R. Fulbright,et al.  Deuterium metabolic imaging (DMI) for MRI-based 3D mapping of metabolism in vivo , 2018, Science Advances.

[3]  James B. Mitchell,et al.  Metabolic and Physiologic Imaging Biomarkers of the Tumor Microenvironment Predict Treatment Outcome with Radiation or a Hypoxia-Activated Prodrug in Mice. , 2018, Cancer research.

[4]  Albert P. Chen,et al.  PET by MRI: Glucose Imaging by 13C-MRS without Dynamic Nuclear Polarization by Noise Suppression through Tensor Decomposition Rank Reduction , 2018, bioRxiv.

[5]  Y. Ling,et al.  Palliative treatment efficacy of glucose inhibition combined with chemotherapy for non-small cell lung cancer with widespread bone and brain metastases: A case report. , 2017, Biomedical reports.

[6]  D. Urban,et al.  Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). , 2017, Journal of medicinal chemistry.

[7]  Nicolas Poté,et al.  Tumor Heterogeneity in Pancreatic Adenocarcinoma , 2017, Pathobiology.

[8]  Gerald C. Chu,et al.  Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism , 2017, Nature Communications.

[9]  M. Falasca,et al.  Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies , 2017, International journal of molecular sciences.

[10]  Jeffrey E. Lee,et al.  Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma , 2017, PloS one.

[11]  E. Collisson,et al.  Stromal cues regulate the pancreatic cancer epigenome and metabolome , 2017, Proceedings of the National Academy of Sciences.

[12]  R. Moffitt,et al.  Hexokinase 2 promotes tumor growth and metastasis by regulating lactate production in pancreatic cancer , 2016, Oncotarget.

[13]  M. Zucchetti,et al.  3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors , 2016, Scientific Reports.

[14]  L. Cantley,et al.  Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion , 2016, Nature.

[15]  Sathesh Bhat,et al.  Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models , 2016, Nature Medicine.

[16]  R. Gillies,et al.  MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts , 2016, PloS one.

[17]  C. Benelli,et al.  The pyruvate dehydrogenase complex in cancer: An old metabolic gatekeeper regulated by new pathways and pharmacological agents , 2016, International journal of cancer.

[18]  B. Faubert,et al.  Metabolic Heterogeneity in Human Lung Tumors , 2016, Cell.

[19]  C. Thompson,et al.  The Emerging Hallmarks of Cancer Metabolism. , 2016, Cell metabolism.

[20]  J. Mayerle,et al.  Approaching Pancreatic Cancer Phenotypes via Metabolomics , 2016 .

[21]  E. Ananieva Targeting amino acid metabolism in cancer growth and anti-tumor immune response. , 2015, World journal of biological chemistry.

[22]  C. H. Nielsen,et al.  The use of dynamic nuclear polarization (13)C-pyruvate MRS in cancer. , 2015, American journal of nuclear medicine and molecular imaging.

[23]  E. Ruppin,et al.  Diversion of aspartate in ASS1-deficient tumors fosters de novo pyrimidine synthesis , 2015, Nature.

[24]  Anneleen Daemen,et al.  Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors , 2015, Proceedings of the National Academy of Sciences.

[25]  M. Hidalgo,et al.  Pancreatic cancer: from state-of-the-art treatments to promising novel therapies , 2015, Nature Reviews Clinical Oncology.

[26]  M. V. Vander Heiden,et al.  Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. , 2015, Cancer research.

[27]  R. Gillies,et al.  Evaluation of the “Steal” Phenomenon on the Efficacy of Hypoxia Activated Prodrug TH-302 in Pancreatic Cancer , 2014, PloS one.

[28]  M. Tempero,et al.  HR‐MAS MRS of the pancreas reveals reduced lipid and elevated lactate and taurine associated with early pancreatic cancer , 2014, NMR in biomedicine.

[29]  James B. Mitchell,et al.  In vivo imaging of tumor physiological, metabolic, and redox changes in response to the anti-angiogenic agent sunitinib: longitudinal assessment to identify transient vascular renormalization. , 2014, Antioxidants & redox signaling.

[30]  Channing J Der,et al.  KRAS: feeding pancreatic cancer proliferation. , 2014, Trends in biochemical sciences.

[31]  A. Joubert,et al.  Tumor cell culture survival following glucose and glutamine deprivation at typical physiological concentrations. , 2014, Nutrition.

[32]  A. Darzi,et al.  Chemical mapping of the colorectal cancer microenvironment via MALDI imaging mass spectrometry (MALDI‐MSI) reveals novel cancer‐associated field effects , 2014, Molecular oncology.

[33]  Y. Kloog,et al.  Metabolism addiction in pancreatic cancer , 2014, Cell Death and Disease.

[34]  R. Deberardinis,et al.  Simultaneous Steady-state and Dynamic 13C NMR Can Differentiate Alternative Routes of Pyruvate Metabolism in Living Cancer Cells* , 2014, The Journal of Biological Chemistry.

[35]  Mikko I. Kettunen,et al.  Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose , 2013, Nature Medicine.

[36]  E. Taylor,et al.  Regulation of pyruvate metabolism and human disease , 2013, Cellular and Molecular Life Sciences.

[37]  Martin O. Leach,et al.  Model Free Approach to Kinetic Analysis of Real-Time Hyperpolarized 13C Magnetic Resonance Spectroscopy Data , 2013, PloS one.

[38]  R. Deberardinis,et al.  The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. , 2013, Molecular cell.

[39]  R. Tomasini,et al.  Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma , 2013, Proceedings of the National Academy of Sciences.

[40]  J. Fangusaro Pediatric High Grade Glioma: a Review and Update on Tumor Clinical Characteristics and Biology , 2012, Front. Oncol..

[41]  Tomoyoshi Soga,et al.  The emerging role of fumarate as an oncometabolite , 2012, Front. Oncol..

[42]  Gerald C. Chu,et al.  Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism , 2012, Cell.

[43]  P. Ward,et al.  Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. , 2012, Cancer cell.

[44]  Damien J. Ferraro,et al.  TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules , 2012, Cancer Chemotherapy and Pharmacology.

[45]  Marc Liesa,et al.  Pancreatic cancers require autophagy for tumor growth. , 2011, Genes & development.

[46]  J. Shea,et al.  Phenotype and Genotype of Pancreatic Cancer Cell Lines , 2010, Pancreas.

[47]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[48]  Douglas B. Evans,et al.  Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice , 2009, Nature Protocols.

[49]  Julien Verrax,et al.  Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. , 2008, The Journal of clinical investigation.

[50]  Jacco D. van Beek,et al.  matNMR: A flexible toolbox for processing, analyzing and visualizing magnetic resonance data in Matlab® , 2007 .

[51]  J. V. van Beek,et al.  matNMR: a flexible toolbox for processing, analyzing and visualizing magnetic resonance data in Matlab. , 2007, Journal of magnetic resonance.

[52]  Manuel Martín-Pastor,et al.  A new general-purpose fully automatic baseline-correction procedure for 1D and 2D NMR data. , 2006, Journal of magnetic resonance.

[53]  K K Jain,et al.  Personalised medicine for cancer: from drug development into clinical practice , 2005, Expert opinion on pharmacotherapy.

[54]  P. Eilers A perfect smoother. , 2003, Analytical chemistry.

[55]  Zhiqiang Weng,et al.  Communication An efficient algorithm for automatic phase correction of NMR spectra based on entropy minimization , 2002 .

[56]  A. Koong,et al.  Pancreatic tumors show high levels of hypoxia. , 2000, International journal of radiation oncology, biology, physics.

[57]  Rasmus Bro,et al.  The N-way Toolbox for MATLAB , 2000 .

[58]  Joos Vandewalle,et al.  On the Best Rank-1 and Rank-(R1 , R2, ... , RN) Approximation of Higher-Order Tensors , 2000, SIAM J. Matrix Anal. Appl..

[59]  C. Garlanda,et al.  Involvement of endothelial PECAM-1/CD31 in angiogenesis. , 1997, The American journal of pathology.

[60]  H. Lyng,et al.  Detection of necrosis in human tumour xenografts by proton magnetic resonance imaging. , 1995, British Journal of Cancer.

[61]  R Gruetter,et al.  Automatic, localized in Vivo adjustment of all first‐and second‐order shim coils , 1993, Magnetic resonance in medicine.

[62]  A. Bax,et al.  Improved linear prediction of damped NMR signals using modified forward-backward linear prediction , 1992 .

[63]  Joel R. Levin,et al.  New developments in pairwise multiple comparisons : some powerful and practicable procedures , 1991 .

[64]  W. Dietrich,et al.  Fast and precise automatic baseline correction of one- and two-dimensional nmr spectra , 1991 .

[65]  J Hennig,et al.  RARE imaging: A fast imaging method for clinical MR , 1986, Magnetic resonance in medicine.

[66]  Ray Freeman,et al.  Broadband Decoupling in High-Resolution Nuclear Magnetic Resonance Spectroscopy , 1984 .

[67]  Ray Freeman,et al.  Supercycles for broadband heteronuclear decoupling , 1982 .

[68]  S. Holm A Simple Sequentially Rejective Multiple Test Procedure , 1979 .