h13C MRI Detects Stimulation of Distal Tumor Glycolytic Flux From Hepatic Ablation in a Breast Metastasis Model

Abstract

Thermal ablation is an effective therapy for liver tumors, however there is evidence that it can stimulate tumor growth at distant sites via the HFG/c-Met pathway, which is also linked to tumor metabolism. We evaluated this effect in vivo using hyperpolarized 13C-pyruvate MRI. Fisher rats were implanted with R3230 rat breast adenocarcinoma cells (n=28) and assigned to either: sham surgery, hepatic radiofrequency ablation (RFA), or hepatic RFA + adjuvant c-Met inhibition with PHA-665752 (single IP dose, 0.83 mg/kg at 24h post-RFA). MRI was performed 24h before and 72h after treatment, and the conversion of 13C-pyruvate into 13C-lactate within each tumor was quantified as lactate:pyruvate ratio (LPR). Hepatic RFA alone resulted in increased growth of the distant tumor compared to sham (0.50±0.13 mm/day and 0.11±0.07 mm/day, respectively; p<0.0001). In the hepatic RFA + adjuvant PHA group, tumor growth rate declined immediately following PHA administration, with a post-treatment growth rate (0.06±0.13 mm/day) similar to the sham group (p=0.28). A significant increase in LPR was seen following hepatic RFA (p=0.02), while LPR was unchanged in the sham (p=0.10) and RFA+PHA (p=0.90) arms. In vivo h13C-pyruvate MRI can detect hepatic RFA-induced increases in lactate conversion within a distant R3230 tumor, which is coupled with relatively increased tumor growth. Adjuvant inhibition of c-Met suppresses these off-target effects. The results highlight the potential for h13C-pyruvate MRI as a potential in vivo tool to detect lesions at risk for off-target RFA stimulation and suggest a possible role for adjuvant c-Met inhibition in such cases.