Objective 1A Creating a Prostate Cancer Tumour Bank
The consortium has begun collecting blood and urine from patients with early stage, locally advanced & metastatic disease and tissue from patients who are undergoing radical prostatectomy or transurethral resection. Ethical approval has been secured at all four hospitals and a common collection protocol has been agreed. A review panel of three consultant pathologists confirms tumour classification by local pathologists. A technique has been developed to securely separate malignant cells from surrounding benign material.
Objective 1B - Understanding Patient Attitudes to Tumour Banking
A patient survey questionnaire to assess patient attitudes to tumour banking and gene profiling has been prepared and is undergoing ethical review. It is hoped that this survey will help inform the clinical research community about attitudes and extent of participation amongst Irish males.
Objective 2 - Identification of Biomarkers of Disease & Disease Progression
Gene-specific DNA hypermethylation may be a characteristic signature of early stage and more aggressive later stage prostate cancer. Bioinformatic approaches have identified a series of genes that are down regulated in prostate cancer. Novel candidates are being tested by methylation sensitive PCR and by bisulphite sequencing assays using quantitative real-time reverse transcriptase PCR. These evaluations are being conducted in collaboration with the National Cancer Institute (US). Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF) will be applied to the serum and urine of a selected patient cohort with a view to identifying distinctive protein signatures. The resulting signatures will then be tested in the remaining collections as a marker of early disease, disease progression and to assess treatment response in prostate cancer clinical trials.
Objective 3 - Correlation of Molecular Markers with Disease Progression
Given the relatively tight genetic pool of the Irish population, the consortium believes that it can develop a molecular classification of disease stage and progression. Bioinformatic analysis is being undertaken on a number of recently published gene datasets including the Inhibitors of Apoptosis Proteins (IAPs) gene class. Real time PCR on RNA isolated from primary cultures demonstrates increased IAP expression in the diseased state. The androgen receptor represents an important target in Prostate Cancer. Differences have been observed from in CAG repeat length number in the androgen receptor (AR) gene in matched androgen dependent and independent cell lines. The consortium will next evaluate repeat length number variation in retrospective material from patients who have shown evidence of progression.
Objective 4 - Exploring Novel Therapeutic Strategies
The primary cell lines representing different disease stages isolated by the consortium will be used to test three novel therapeutic approaches.
RNA Interference for the Inhibition of Specific Gene Products
Gene Delivery of Specific Genes to Increase Susceptibility to Existing Therapies
Small molecule agents that Interfere with Cell Death Pathways
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