Combined biochemical and biophysical imaging biomarkers for characterization of tumor metabolism and response to therapy

• Applicant: Professor Dr. Franz Schilling
• Subject Area: Medical Physics, Biomedical Technology
• Term: from 2017 to 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391523415

• Final Report Year: 2024

Final Report Abstract

Imaging biomarkers enable a comprehensive characterization of tissue providing functional, physiological, metabolic, cellular and molecular information beyond anatomical structures. For cancer patients, specific non-invasive imaging strategies for early-stage detection, tumor phenotyping and evaluation of response to therapy are not available at a satisfactory level, creating a pressing need for advanced technologies. In this project, I aimed to develop two novel non-invasive imaging techniques to measure extracellular pH and transmembrane water permeability in tumors. First, by using pH imaging, we characterized the acidic tumor microenvironment caused by aberrant metabolism and studied the link to tumor aggressiveness. Second, we tested whether imaging of transmembrane water permeability reports on early stages of cell death, thereby providing an early evaluation technology to detect whether a drug has hit its target before an anatomical reduction in tumor size is recognizable. Specifically, we have advanced current methods for non-invasive MRI pH imaging by introducing hyperpolarized [1,5-13C2]Z-OMPD as a new pH sensor and new MRI acquisition schemes for pH imaging. Faster and more sensitive protocols for transmembrane water exchange MRI measurements in vitro and in vivo have been developed allowing mapping of the apparent exchange rate (AXR). The feasibility for clinical translation of both methods has been demonstrated by AXR measurements in human patients and pH imaging in feline patients on a clinical scanner. Both pH imaging and AXR mapping can help to elucidate tumor biology, allowing to characterize tumor metabolic phenotype and to detect early treatment response non-invasively.

Publications

• Ab Initio Simulation of pH-Sensitive Biomarkers in Magnetic Resonance Imaging. The Journal of Physical Chemistry A, 122(40), 7983-7990.
  Köcher, Simone S.; Düwel, Stephan; Hundshammer, Christian; Glaser, Steffen J.; Schilling, Franz; Granwehr, Josef & Scheurer, Christoph
  
• Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules. Sensors, 18(2), 600.
  Hundshammer, Christian; Düwel, Stephan; Ruseckas, David; Topping, Geoffrey; Dzien, Piotr; Müller, Christoph; Feuerecker, Benedikt; Hövener, Jan B.; Haase, Axel; Schwaiger, Markus; Glaser, Steffen J. & Schilling, Franz
  
• Acquisition strategies for spatially resolved magnetic resonance detection of hyperpolarized nuclei. Magnetic Resonance Materials in Physics, Biology and Medicine, 33(2), 221-256.
  Topping, Geoffrey J.; Hundshammer, Christian; Nagel, Luca; Grashei, Martin; Aigner, Maximilian; Skinner, Jason G.; Schulte, Rolf F. & Schilling, Franz
  
• pH Dependence ofT1for13C‐Labelled Small Molecules Commonly Used for Hyperpolarized Magnetic Resonance Imaging. ChemPhysChem, 20(6), 798-802.
  Hundshammer, Christian; Grashei, Martin; Greiner, Alexandra; Glaser, Steffen J. & Schilling, Franz
  
• Dynamic 2D and 3D mapping of hyperpolarized pyruvate to lactate conversion in vivo with efficient multi‐echo balanced steady‐state free precession at 3 T. NMR in Biomedicine, 33(6).
  Müller, Christoph A.; Hundshammer, Christian; Braeuer, Miriam; Skinner, Jason G.; Berner, Stephan; Leupold, Jochen; Düwel, Stephan; Nekolla, Stephan G.; Månsson, Sven; Hansen, Adam E.; von Elverfeldt, Dominik; Ardenkjaer‐Larsen, Jan H.; Schilling, Franz; Schwaiger, Markus; Hennig, Jürgen & Hövener, Jan‐Bernd
  
• Hyperpolarized 13C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC. Scientific Reports, 11(1).
  Bliemsrieder, Elisabeth; Kaissis, Georgios; Grashei, Martin; Topping, Geoffrey; Altomonte, Jennifer; Hundshammer, Christian; Lohöfer, Fabian; Heid, Irina; Keim, Dominik; Gebrekidan, Selamawit; Trajkovic-Arsic, Marija; Winkelkotte, A. M.; Steiger, Katja; Nawroth, Roman; Siveke, Jens; Schwaiger, Markus; Makowski, Marcus; Schilling, Franz & Braren, Rickmer
  
• Hyperpolarized 13C Spectroscopy with Simple Slice-and-Frequency-Selective Excitation. Biomedicines, 9(2), 121.
  Topping, Geoffrey J.; Heid, Irina; Trajkovic-Arsic, Marija; Kritzner, Lukas; Grashei, Martin; Hundshammer, Christian; Aigner, Maximilian; Skinner, Jason G.; Braren, Rickmer & Schilling, Franz
  
• pH Dependence of T2 for Hyperpolarizable 13C-Labelled Small Molecules Enables Spatially Resolved pH Measurement by Magnetic Resonance Imaging. Pharmaceuticals, 14(4), 327.
  Grashei, Martin; Hundshammer, Christian; van Heijster, Frits H. A.; Topping, Geoffrey J. & Schilling, Franz
  
• Conversion of Hyperpolarized [1-13C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment. Cancers, 14(7), 1845.
  Grashei, Martin; Biechl, Philipp; Schilling, Franz & Otto, Angela M.
  
• Functional noninvasive detection of glycolytic pancreatic ductal adenocarcinoma. Cancer & Metabolism, 10(1).
  Heid, Irina; Münch, Corinna; Karakaya, Sinan; Lueong, Smiths S.; Winkelkotte, Alina M.; Liffers, Sven T.; Godfrey, Laura; Cheung, Phyllis F. Y.; Savvatakis, Konstantinos; Topping, Geoffrey J.; Englert, Florian; Kritzner, Lukas; Grashei, Martin; Tannapfel, Andrea; Viebahn, Richard; Wolters, Heiner; Uhl, Waldemar; Vangala, Deepak; Smeets, Esther M. M. ... & Siveke, Jens T.
  
• Prediction of multiple pH compartments by deep learning in magnetic resonance spectroscopy with hyperpolarized 13C-labelled zymonic acid. EJNMMI Research, 12(1).
  Fok, Wai-Yan Ryana; Grashei, Martin; Skinner, Jason G.; Menze, Bjoern H. & Schilling, Franz
  
• In Vivo Metabolic Imaging of [1‐13C]Pyruvate‐d3 Hyperpolarized By Reversible Exchange With Parahydrogen**. Angewandte Chemie International Edition, 62(36).
  de Maissin, Henri; Groß, Philipp R.; Mohiuddin, Obaid; Weigt, Moritz; Nagel, Luca; Herzog, Marvin; Wang, Zirun; Willing, Robert; Reichardt, Wilfried; Pichotka, Martin; Heß, Lisa; Reinheckel, Thomas; Jessen, Henning J.; Zeiser, Robert; Bock, Michael; von Elverfeldt, Dominik; Zaitsev, Maxim; Korchak, Sergey; Glöggler, Stefan ... & Schmidt, Andreas B.
  
• New Horizons in Hyperpolarized 13C MRI. Molecular Imaging and Biology, 26(2), 222-232.
  Chaumeil, Myriam M.; Bankson, James A.; Brindle, Kevin M.; Epstein, Shdema; Gallagher, Ferdia A.; Grashei, Martin; Guglielmetti, Caroline; Kaggie, Joshua D.; Keshari, Kayvan R.; Knecht, Stephan; Laustsen, Christoffer; Schmidt, Andreas B.; Vigneron, Daniel; Yen, Yi-Fen & Schilling, Franz
  
• Parahydrogen-Polarized Fumarate for Preclinical in Vivo Metabolic Magnetic Resonance Imaging. Journal of the American Chemical Society, 145(10), 5960-5969.
  Gierse, Martin; Nagel, Luca; Keim, Michael; Lucas, Sebastian; Speidel, Tobias; Lobmeyer, Tobias; Winter, Gordon; Josten, Felix; Karaali, Senay; Fellermann, Maximilian; Scheuer, Jochen; Müller, Christoph; van Heijster, Frits; Skinner, Jason; Löffler, Jessica; Parker, Anna; Handwerker, Jonas; Marshall, Alastair; Salhov, Alon ... & Knecht, Stephan
  
• Parahydrogen‐Polarized [1‐13C]Pyruvate for Reliable and Fast Preclinical Metabolic Magnetic Resonance Imaging. Advanced Science, 10(30).
  Nagel, Luca; Gierse, Martin; Gottwald, Wolfgang; Ahmadova, Zumrud; Grashei, Martin; Wolff, Pascal; Josten, Felix; Karaali, Senay; Müller, Christoph A.; Lucas, Sebastian; Scheuer, Jochen; Müller, Christoph; Blanchard, John; Topping, Geoffrey J.; Wendlinger, Andre; Setzer, Nadine; Sühnel, Sandra; Handwerker, Jonas; Vassiliou, Christophoros ... & Schwartz, Ilai
  
• PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma. Nature Cancer, 4(10), 1508-1525.
  Wartewig, Tim; Daniels, Jay; Schulz, Miriam; Hameister, Erik; Joshi, Abhinav; Park, Joonhee; Morrish, Emma; Venkatasubramani, Anuroop V.; Cernilogar, Filippo M.; van Heijster, Frits H. A.; Hundshammer, Christian; Schneider, Heike; Konstantinidis, Filippos; Gabler, Judith V.; Klement, Christine; Kurniawan, Henry; Law, Calvin; Lee, Yujin; Choi, Sara ... & Ruland, Jürgen
  
• Repeatability and reproducibility of apparent exchange rate measurements in yeast cell phantoms using filter-exchange imaging. Magnetic Resonance Materials in Physics, Biology and Medicine, 36(6), 957-974.
  Schillmaier, Mathias; Kaika, Athanasia; Topping, Geoffrey J.; Braren, Rickmer & Schilling, Franz
  
• Simultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarized 13C-labelled Z-OMPD. Nature Communications, 14(1).
  Grashei, Martin; Wodtke, Pascal; Skinner, Jason G.; Sühnel, Sandra; Setzer, Nadine; Metzler, Thomas; Gulde, Sebastian; Park, Mihyun; Witt, Daniela; Mohr, Hermine; Hundshammer, Christian; Strittmatter, Nicole; Pellegata, Natalia S.; Steiger, Katja & Schilling, Franz
  
• Spectrally selective bSSFP using off‐resonant RF excitations permits high spatiotemporal resolution 3D metabolic imaging of hyperpolarized [1‐13C]Pyruvate‐to‐[1‐13C]lactate conversion. Magnetic Resonance in Medicine, 90(3), 894-909.
  Skinner, Jason G.; Topping, Geoffrey J.; Nagel, Luca; Heid, Irina; Hundshammer, Christian; Grashei, Martin; van Heijster, Frits H. A.; Braren, Rickmer & Schilling, Franz
  
• Current methods for hyperpolarized [1‐13C]pyruvate MRI human studies. Magnetic Resonance in Medicine, 91(6), 2204-2228.
  Larson, Peder E. Z.; Bernard, Jenna M. L.; Bankson, James A.; Bøgh, Nikolaj; Bok, Robert A.; Chen, Albert P.; Cunningham, Charles H.; Gordon, Jeremy W.; Hövener, Jan‐Bernd; Laustsen, Christoffer; Mayer, Dirk; McLean, Mary A.; Schilling, Franz; Slater, James B.; Vanderheyden, Jean‐Luc; von Morze, Cornelius; Vigneron, Daniel B. ... & Xu, Duan
  
• Filter‐exchange spectroscopy is sensitive to gradual cell membrane degradation. NMR in Biomedicine, 37(11).
  Kaika, Athanasia; Topping, Geoffrey J.; Nagel, Luca & Schilling, Franz
  
• Quo Vadis Hyperpolarized 13C MRI?. Zeitschrift für Medizinische Physik, 35(1), 8-32.
  Wodtke, Pascal; Grashei, Martin & Schilling, Franz