The cholinic phenotype, characterized by elevated
phosphocholine and a high production of total-
choline (tCho)-containing metabolites, is a metabolic hallmark of
cancer. It can be exploited for targeted
therapy. Non-invasive imaging
biomarkers are required to evaluate an individual's response to targeted
anticancer agents that usually do not rapidly cause
tumor shrinkage. Because metabolic changes can manifest at earlier stages of
therapy than changes in
tumor size, the aim of the current study was to evaluate (1)H-MRS and diffusion-weighted MRI (DW-MRI) as markers of
tumor response to the modulation of the
choline pathway in mammary
tumor xenografts. Inhibition of
choline kinase activity was achieved with the direct pharmacological inhibitor
H-89, indirect inhibitor
sorafenib and down-regulation of
choline-kinase α (ChKA) expression using specific
short-hairpin RNA (
shRNA). While all three strategies significantly decreased tCho
tumor content in vivo, only
sorafenib and anti-ChKA
shRNA significantly repressed
tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced
necrosis and inhibition of the
tumor growth in
sorafenib treated mice, while the absence of change in ADC values in
H89 treated mice predicted the absence of effect in terms of
tumor necrosis and
tumor growth. In conclusion, (1)H-choline spectroscopy can be useful as a pharmacodynamic
biomarker for
choline targeted agents, while DW-MRI can be used as an early marker of effective
tumor response to
choline targeted
therapies. DW-MRI combined to
choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of
tumor response to
therapies targeting
choline signaling.