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Title: Identifying mechanisms of androgen receptor variant regulation in models of castrate resistant prostate cancer
Author: Jones, Dominic Louis
ISNI:       0000 0004 6424 7619
Awarding Body: University of Newcastle upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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Current treatment options for the management of prostate cancer (PC) attempt to abrogate androgen receptor (AR) signalling by reducing circulating androgens in addition to inhibiting AR-ligand binding, collectively termed androgen deprivation therapy (ADT). Although initially efficacious, most patients often relapse with a more aggressive form of the disease termed castrate resistant prostate cancer (CRPC). A number of aberrations of AR signalling have been identified which have been shown to provide resistance to current therapeutic tools. One particular mechanism is the emergence of androgen receptor splice variants (AR-Vs) which lack the ligand bind domain of the receptor and are refractory to current ADT but retain transcriptional activity and can drive androgenic signalling and cell growth even in androgen deprived conditions. There are currently no clinically approved agents for targeted inhibition of AR-Vs, therefore, they represent a major clinical obstacle in the management of CRPC. Identification of regulatory networks responsible for modulating the activity of AR-Vs may present a means to inhibit their function. Previous studies have demonstrated the importance of co-regulatory proteins for the modulation of AR function, including proteins that directly modify the receptor altering receptor function. The aim of this study is to interrogate mechanisms of androgen receptor variant regulation through two approaches: firstly, a candidate approach, investigating the role of known full length AR regulators, including CDK1, CDK.9 and Aurora A kinase. Secondly, by mass spectrometry, identify novel interacting proteins of AR-Vs and interrogate their regulatory function. This approach has demonstrated that AR-Vs appear to be regulated in a manner distinct from the full length receptor. Unlike AR full length (AR-fl), AR-Vs do not require CDK1/9 mediated phosphorylation of serine-81 to function. Similarly Aurora A kinase mediated phosphorylation of the AR-Vs is not required, however, as a mechanism distinct from AR-fl regulation, Aurora A is able to modulate AR-V expression through disrupting splicing of AR pre-mRNA. Mass spectrometry of AR-V complexes has provided a comprehensive list of interacting proteins with further interrogation into the role of two identified proteins: RUVBL1 and CCAR2 proteins as potential AR-V regulatory proteins. Both RUVBL1 and CCAR2 regulate a significant number of AR-V target genes in models of CRPC demonstrating their ability to coactive AR-V function. Taken together, this study interrogates the importance of a number of important AR-V regulatory mechanism and provides potential therapeutic targets for the management of AR-V activity in CRPC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available