Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy.

Jack Ja Van Asten,Riyas Vettukattil,Tone F Bathen,Fijs Van Leeuwen,Sven Rottenberg,Arend Heerschap,Tessa Buckle

doi:10.1186/s12967-015-0458-4

Abstract

BackgroundDocetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer.MethodologyHigh resolution magic angle spinning (HRMAS) 1H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm.ResultsThe HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation.ConclusionsRelative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment.

Highlights

Docetaxel is one of the most frequently used drugs to treat breast cancer
Metabolic differences between docetaxel resistant and sensitive tumors before treatment A comparison of spectra obtained by 1H High resolution magic angle spinning (HRMAS) Magnetic resonance spectroscopy (MRS) of resistant and sensitive breast cancer tissue shows some clear spectral differences between 3.1 and 3.4 ppm (Figure 1A)
In conclusion, this study shows that 1H HRMAS MRS can distinguish between docetaxel sensitive and resistant BRCA1-mutated mouse mammary tumors because they are metabolically distinct

Summary

Introduction

Docetaxel is one of the most frequently used drugs to treat breast cancer. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer. Methodology: High resolution magic angle spinning (HRMAS) 1H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Docetaxel has well established benefits in the treatment of breast cancer [2,3]. Molecular and metabolic biomarkers may identify docetaxel resistant and sensitive subjects and stratify patients for better treatment options. Far there are no reliable methods to predict the response to docetaxel prior to treatment or to identify the patients who will most likely benefit from therapy. Like altered metabolism or apoptosis may be easier to monitor shortly after docetaxel-induced stress

Objectives

Methods

Results

Discussion

Conclusion