Abstract 2854: The potential of hyperpolarized 13-C magnetic resonance spectroscopy to monitor the effect of combretastatin based vascular disrupting agents
Authors: Iversen Ane B. , Busk Morten , Bertelsen Lotte B. , Laustsen Christoffer , Munk Ole L. , Nielsen Thomas , Wittenborn Thomas R. , Bussink Johan , Lok Jasper , Stodkilde-Jorgensen Hans , Horsman Michael R. 
Published: July 2017

Purpose: Targeting tumor vasculature using vascular disrupting agents (VDAs) is an attractive therapy. These agents induce rapid physiological changes long before any growth inhibitory effects become apparent. Detecting these early changes should allow us to predict anti-tumor effects. Hyperpolarized ¹³C magnetic resonance spectroscopy (HPMRS) allows dynamic measurements of the metabolism of 13C-labeled substrates and may be a new approach for reliably monitoring early effects of VDAs. The aim of this study was to investigate the potential of HPMRS to achieve this in a pre-clinical model.

Methods: Mice bearing 200 cubic mm foot implanted C3H mammary carcinomas were intraperitoneally injected with combretastatin-A4-phosphate (CA4P) or the A1 analogue OXi4503. Tumor response was assessed by determining necrosis development, measured histologically 24-hours after treatment, and tumor growth time (TGT; time to reach 5 times treatment volume). Estimates of tumor perfusion and metabolism were performed 3h (CA4P) and 6h (OXi4503) after treatment. Perfusion was measured from Hoechst 33342 uptake in histological sections and by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) at 7-Tesla. Metabolic changes were assessed following intravenous injection of hyperpolarized [1-¹³C]pyruvate and observing the conversion to lactate with HPMRS in a 9.4-Tesla scanner. Additional mice were positron emission tomography (PET) scanned using a Mediso nanoScan PET/MRI scanner following administration of fluorodeoxyglucose (FDG). Statistical comparisons were made using a one-way analysis of variance (ANOVA), with significance level of p&lt;0.05.

Results: A dose response relationship was found between injected drug doses and both tumor necrosis induction and TGT, with OXi4503 having a larger effect than CA4P. Two equally effective doses were selected for further analysis (250 mg/kg for CA4P and 50 mg/kg for OXi4503). Both drugs significantly decreased perfusion relative to controls; the respective mean (with 1 SE) values for CA4P and OXi4503 were decreased to 57% (50-64) and 38% (28-48) using Hoechst 33342, and 61% (57-65) and 61% (54-68) using DCE-MRI. FDG uptake (mean tumor-to-brain ratio) also significantly reduced to 43% (33-53) and 33% (25-41) for CA4P and OXi4503, respectively. However, an unaltered pyruvate to lactate ratio was found; the values being 98% (89-107) for CA4P and 113% (102-124) for OXi4503.

Conclusion: No change in the HPMRS values was observed, despite changes in all other parameters, indicating that the metabolic fate of pyruvate remains unaltered despite reduced delivery of oxygen and nutrients. This could be because our data provides measures of whole-tumor mean responses that include a viable metabolically unaltered tumor rim and a tumor core with no blood flow (i.e., no pyruvate delivery) following VDA treatment.

Citation Format: Ane B. Iversen, Morten Busk, Lotte B. Bertelsen, Christoffer Laustsen, Ole L. Munk, Thomas Nielsen, Thomas R. Wittenborn, Johan Bussink, Jasper Lok, Hans Stodkilde-Jorgensen, Michael R. Horsman. The potential of hyperpolarized 13-C magnetic resonance spectroscopy to monitor the effect of combretastatin based vascular disrupting agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2854. doi:10.1158/1538-7445.AM2017-2854