title: Monitoring chemotherapeutic response by hyperpolarized 13C-fumarate MRS and diffusion MRI.
abstract: Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by (13)C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized (13)C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, (13)C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration.
authors.affiliation: Authors' Affiliations: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium; and Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mignion
authors.forename: Prasanta
authors.initials: P
authors.lastname: Dutta
authors.forename: Gary V
authors.initials: GV
authors.lastname: Martinez
authors.forename: Parastou
authors.initials: P
authors.lastname: Foroutan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D002247:Carbon Isotopes; D045744:Cell Line, Tumor; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D005260:Female; D005650:Fumarates; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002247:Carbon Isotopes; D005650:Fumarates