Zhu, Yanan;
(2024)
Investigating CEST MRI for the assessment of response to proteasome inhibitor treatment in solid tumours.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Proteasome inhibitors (PIs) are the standard of care for several blood-borne cancers with the potential for treating solid tumours. In colorectal cancer, noninvasive biomarkers of treatment response allow early patient stratification and treatment personalisation. The PhD project investigated whether measurements from chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) alongside conventional MRI can be used to detect altered protein concentration and anti-tumour effects in mouse colorectal tumour xenograft models in response to PI. Preliminary experiments evaluated the rodent models’ in vivo tolerance to the PI, Ixazomib. The differential sensitivity of colorectal carcinoma cells to Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute (single dose at three concentrations over five days) and chronic (repeat dose at one concentration over three weeks) in vivo responses to Ixazomib were investigated using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T1, T2). These responses were further evaluated ex vivo with the known histological markers (caspase-3 and GADD34) and Bradford assay for protein quantification. CEST signals from amides and amines increased with Ixazomib dose in colorectal cancer xenografts, reflecting PI-induced protein accumulation. The cell lines differed in their in vitro and vivo sensitivity to Ixazomib, which was also shown by inhibited tumour volume growth and increased ADC. These measurements demonstrated Ixazomib-induced tumour cell death, evidenced by increased apoptosis marker caspase-3. A mild stimulation in tumour growth was observed at low Ixazomib doses in vitro and in vivo. The results identify CEST MRI as a promising method for safely and noninvasively monitoring responses to PI treatment and for stratifying sensitivity between tumour types.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating CEST MRI for the assessment of response to proteasome inhibitor treatment in solid tumours |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10195514 |
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