Abstract
Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T1, T2). These responses were further evaluated with the known histological markers for Ixazomib and Bradford assay ex vivo. The CEST signal from amides and amines increased in proportion to Ixazomib dose in colorectal cancer xenografts. The cell lines differed in their sensitivity to Ixazomib, which was reflected in the MRI measurements. A mild stimulation in tumor growth was observed at low Ixazomib doses. Our results identify CEST MRI as a promising method for safely and noninvasively monitoring disrupted tumor protein homeostasis induced by proteasome inhibitor treatment, and for stratifying sensitivity between tumor types.
Highlights
Loss of protein homeostasis is associated with a range of pathological conditions including most forms of dementia[1], amyloidosis[2] and cancers[3]
Alongside CEST, we evaluated a range of quantitative, noninvasive magnetic resonance imaging (MRI) measurements, in LS174T and SW1222 xenograft models of human colorectal carcinoma
Both cell lines exhibited a stimulatory response at low doses (
Summary
Loss of protein homeostasis is associated with a range of pathological conditions including most forms of dementia[1], amyloidosis[2] and cancers[3]. CEST image contrast can be tuned to reflect the exchange of protons between water and various chemical groups, including amides (in protein backbones), amines, guanidinium and hydroxyls[20]. This enables the small signal from solutes containing such groups to be amplified via the much larger water pool signal. In vivo measurements of acute (up to 72 hours) dosing with Ixazomib, at three different dose concentrations, were undertaken and compared with gold-standard histological measures[5,22,23] Biological validation studies, such as undertaken here, are a vital component of the roadmap for the translation of imaging biomarkers into the clinic[24]. Ixazomib has shown promise in solid tumor rodent models, including colorectal tumors[9,10,11,12,13,14]
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