Monitoring chemotherapeutic response by hyperpolarized 13C-fumarate MRS and diffusion MRI .

Cancer Research

PubMedID: 24285723

Mignion L, Dutta P, Martinez GV, Foroutan P, Gillies RJ, Jordan BF. Monitoring chemotherapeutic response by hyperpolarized 13C-fumarate MRS and diffusion MRI . Cancer Res. 2014;74(3):686-94.
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 non-invasive imaging protocols to monitor responses to Sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular cancers. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by 13C-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, since viable cells act as a diffusion barrier in tissue. For these reasons, we assessed Sorafenib responses using hyperpolarized (HP) 13C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer where daily administration of Sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of HP fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2-5 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. Histological analyses confirmed cell death in the Sorafenib-treated cohort. Notably, 13C-pyruvate-to-lactate conversion was not affected by Sorafenib in the breast cancer model examined. Our results illustrate how combining HP-substrates with DW-MRI can allow non-invasive monitoring of targeted therapeutic responses at relatively early times after drug administration.