Investigating circulating miRNAs as predictors of therapeutic response in metastatic castration-resistant prostate cancer
File(s)
Author(s)
Shibakawa, Akifumi
Type
Thesis
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is advanced prostate cancer (PCa) that has developed resistance to first-line androgen deprivation therapies. For mCRPC, several treatments are available, but the response rate is usually low (<50%) for any treatment. Therefore, a biomarker that can predict response to a particular treatment will be beneficial as predicted non-responders could be offered alternative treatments that may be more effective and avoid unnecessary side effects.
microRNAs (miRs) are a class of short non-coding RNA and circulating miRs (c-miRs) refer to extracellular miRs found in the blood. c-miRs hold many characteristics of an ideal biomarker, such as high stability, and have been investigated as biomarkers in various diseases including PCa. We hypothesised that pre-treatment levels of specific c-miRs in mCRPC patients can predict their response to Cabazitaxel (CBZ), which is a taxane chemotherapy used in treatment for mCRPC.
PROSELICA is a clinical trial, in which mCRPC patients were treated with CBZ as second-line chemotherapy. Using pre-treatment plasma from PROSELICA, the levels of 41 potentially CBZ response associated c-miRs were measured in 21 responders and 21 non- responders with a Fireplex assay. Compared to responders, non-responders had significantly higher pre-treatment levels of 8 c-miRs, including miR-132-3p. This up-regulation of c-miRs could be technically validated using modified qPCR. Individually, these 8 up-regulated c- miRs had CBZ response predictive power with AUROC around or greater than 0.7 and 7 of them were also shown to be prognostic of overall survival in CBZ-treated mCRPC patients.
Next, we decided to validate the findings in separate 108 patients from PROSELICA. Although the predictive power of these c-miRs were not confirmed, up-regulation of miR- 132-3p in non-responders and the prognostic power of 7 c-miRs were validated.
Lastly, the potential sources of these 8 c-miRs were explored. Using publicly available datasets, the expression of these 8 c-miRs were confirmed in CRPC tissues. Subsequently, the release of these c-miRs from tumours was observed in vitro using Explanted tissues from prostate biopsies.
In conclusion, specific c-miRs are prognostic and potentially predictive of CBZ response in mCRPC patients and these prognostic/predictive c-miRs may come from tumours, suggesting they may play a role in CBZ-response in tumours.
microRNAs (miRs) are a class of short non-coding RNA and circulating miRs (c-miRs) refer to extracellular miRs found in the blood. c-miRs hold many characteristics of an ideal biomarker, such as high stability, and have been investigated as biomarkers in various diseases including PCa. We hypothesised that pre-treatment levels of specific c-miRs in mCRPC patients can predict their response to Cabazitaxel (CBZ), which is a taxane chemotherapy used in treatment for mCRPC.
PROSELICA is a clinical trial, in which mCRPC patients were treated with CBZ as second-line chemotherapy. Using pre-treatment plasma from PROSELICA, the levels of 41 potentially CBZ response associated c-miRs were measured in 21 responders and 21 non- responders with a Fireplex assay. Compared to responders, non-responders had significantly higher pre-treatment levels of 8 c-miRs, including miR-132-3p. This up-regulation of c-miRs could be technically validated using modified qPCR. Individually, these 8 up-regulated c- miRs had CBZ response predictive power with AUROC around or greater than 0.7 and 7 of them were also shown to be prognostic of overall survival in CBZ-treated mCRPC patients.
Next, we decided to validate the findings in separate 108 patients from PROSELICA. Although the predictive power of these c-miRs were not confirmed, up-regulation of miR- 132-3p in non-responders and the prognostic power of 7 c-miRs were validated.
Lastly, the potential sources of these 8 c-miRs were explored. Using publicly available datasets, the expression of these 8 c-miRs were confirmed in CRPC tissues. Subsequently, the release of these c-miRs from tumours was observed in vitro using Explanted tissues from prostate biopsies.
In conclusion, specific c-miRs are prognostic and potentially predictive of CBZ response in mCRPC patients and these prognostic/predictive c-miRs may come from tumours, suggesting they may play a role in CBZ-response in tumours.
Version
Open Access
Date Issued
2019-04
Date Awarded
2019-07
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Bevan, Charlotte
Fletcher, Claire
de Bono, Johann
Sponsor
Movember/PCUK
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)