Trujillo Alba, Blanca Lourdes;
(2023)
Leveraging sequential plasma samples and post-mortem tissue samples to characterise the mechanisms of resistance in metastatic prostate cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Despite the approval of several treatments conferring an overall survival benefit in metastatic prostate cancer patients, the mechanisms of resistance to these drugs are not well understood and unfortunately it remains a lethal disease. I hypothesised that analysing metastatic prostate cancer patients through collection of multiple longitudinal blood samples coupled to characterisation of post-mortem samples would identify such resistance mechanisms. To that end, I developed and analysed in an N=1 manner a cohort of 10 metastatic prostate cancer patients by first, establishing a platform for intensive blood sampling and archival tissue and clinical data collection and second, by collecting multi-region post-mortem samples in an established prostate cohort under the PEACE post-mortem study. I generated high coverage targeted capture data for a total number of 308 samples (13 archival, 97 plasma and 198 post-mortem) using a prostate-specific assay and performed genomic analysis using a tool optimized for accurate calling of allele specific copy number (CN) alterations. The data generated showed that CN assessment at an allele-specific level, helps understanding the variable responses to PARP inhibitors of DNA Damage Repair (DDR) aberrant patients. Further data in this thesis, showed that lethal metastases clustered into two/three distinct groups based on their autosomal CN alterations. Furthermore, the clonal evolution could be tracked longitudinally using circulating tumour DNA (ctDNA) over sequential treatment lines which preceded radiological progression, and I identified treatment-related genomic aberrations that emerged or regressed over time. However, despite the regression of clones in plasma, these could still be identified in post-mortem samples. Also, although ctDNA represented the bulk of the metastatic disease, subclonal aberrations private to a few metastatic sites could be missed in plasma. Analysis of archival diagnostic samples confirmed putatively truncal events identified at post-mortem and plasma. I identified a positive correlation between circulating cell-free DNA (ccfDNA) and ctDNA for patients receiving androgen receptor signalling inhibitors (ARSI) in contrast to taxane chemotherapies. Finally, I observed that patients with extensive lymph node disease in the absence of liver metastases shed significantly lower fractions of ctDNA in blood. In conclusion, the results of this thesis confirm that genomic analysis of multiple plasma and post-mortem samples allowed for spatial and longitudinal clone characterization allowing for a deeper understanding of mechanisms of resistance in lethal prostate cancer patients.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Leveraging sequential plasma samples and post-mortem tissue samples to characterise the mechanisms of resistance in metastatic prostate cancer |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10180851 |
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