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Title: Androgen receptor gene amplification in bone metastases from hormone-refractory prostate cancer
Author: Brown, Richard S. D.
ISNI:       0000 0001 3502 0237
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2003
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The mechanisms for hormone-refractory prostate cancer (HRPC) are incompletely understood. There is no effective therapy for HRPC and new treatment approaches are needed. One postulated mechanism for the development of HRPC is androgen receptor (AR) gene amplification in prostate cancers treated with androgen deprivation or anti-androgen therapy. By increasing the availability of nuclear androgen receptors, cells with AR gene amplification may continue to more efficiently utilise low levels of circulating androgen found after castration. The AR gene amplification may therefore confer a growth advantage for tumour cells showing these changes, compared to cells without such a mutation. Androgen receptor gene amplification has been demonstrated to occur in approximately one-third of patients with either local tumour recurrences from HRPC or at the sites of metastatic disease studied to date. Samples from bone metastases in patients with HRPC are difficult to both obtain and work with and androgen receptor gene amplification has not been studied or demonstrated in bone metastases from HRPC. This thesis describes a method for obtaining bone metastases from HRPC patients using bone marrow trephine biopsies, targeted by diagnostic bone scans. The prevalence of AR gene amplification in the metastases obtained is examined. Data on DNA preservation for fluorescent in situ hybridisation (FISH) studies to demonstrate AR gene amplification following acid decalcification of bone samples is presented. Unsuccessful attempts at studying the HRPC samples using comparative genomic hybridization (CGH) are detailed. Androgen receptor immunohistochemical (IHC) expression in these bone metastases is also assessed to evaluate if IHC can identify tumours exhibiting AR gene amplification. Patients with AR gene amplification at primary tumour progression may respond more favourably to subsequent combined androgen blockade. Demonstrating AR gene amplification at a clinically important disease site, may allow sub-classification of HRPC patients who can benefit from this or alternative therapeutic strategies targeted at AR gene amplification.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available