title: Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism.
abstract: The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1)H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1)H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling.
authors.affiliation: Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 73 Box B1.73.08, Brussels, Belgium.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mignion
authors.affiliation: Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 73 Box B1.73.08, Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Danhier
authors.affiliation: Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 73 Box B1.73.08, Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Magat
authors.affiliation: Pole of Pharmacology, Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain (UCL), Avenue Mounier, 52 Box B1.53.09, Brussels, Belgium.
authors.forename: Paolo E
authors.initials: PE
authors.lastname: Porporato
authors.affiliation: Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 72 Box B1.72.01, Brussels, Belgium.
authors.forename: Julien
authors.initials: J
authors.lastname: Masquelier
authors.affiliation: Center for Molecular Imaging, Radiotherapy and Oncology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Avenue Hippocrate, 55 Box B1.55.02, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gregoire
authors.affiliation: Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 72 Box B1.72.01, Brussels, Belgium.
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.affiliation: Pole of Pharmacology, Institut De Recherche Expérimentale Et Clinique (IREC), Université Catholique De Louvain (UCL), Avenue Mounier, 52 Box B1.53.09, Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.affiliation: Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 73 Box B1.73.08, Brussels, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
authors.affiliation: Biomedical Magnetic Resonance Group, Louvain Drug Research Institute, Université Catholique De Louvain (UCL), Avenue Mounier, 73 Box B1.73.08, Brussels, Belgium.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D005260:Female; D064593:Heterografts; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011522:Protons; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011522:Protons; D013449:Sulfonamides; D009536:Niacinamide; D000077157:Sorafenib; D002797:Choline Kinase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: choline signaling; magnetic resonance imaging; marker of response; targeted agents