Urology
 Prof Colleen Nelson
Prostate Cancer Biomarkers
Identify Biomarkers to Discriminate Indolent from Aggressive Prostate Cancer
In this proposal we will address these critical issues in prostate cancer management by comprehensively defining and comparing on a genome-wide scale genetic lesions in prostate cancer specimens using ultra high density array CGH (aCGH) in the following Objectives:
- Characterize the extent of heterogeneity of multi-focal cancer within a patient by isolating foci from whole mount prostate sections from radical prostatectomies;
- Compare genetic lesions from prostate cancer patients with clinically significant CaP prior to the PSA era with CaP detected in a contemporary cohort of patients identified by PSA without other clinical features; and
- Compare genetic signatures of radical prostatectomy patients from PAH with patients that have been treated with androgen ablation or androgen ablation and taxotere prior to radical prostatectomy collected in Vancouver which will illuminate genetic lesions associated with treatment resistance.
RATIONALE
To characterize the multifocality — The current management of prostate cancer diagnosis and prognosis relies on multiple biopsies to guide treatment decisions, however in fact because of the multifocal nature of CaP, these biopsies often represent different tumor phenotypes each with unique sets of genetic lesions. In the era of targeted therapies arising it is imperative we understand the extent of this inherent intra-patient heterogeneity. At PAH we are advantaged by the practice of embedding entire prostate specimens, as opposed to pathological blocks limited to suspected tumor foci.
Finding markers of indolence — Although advances in CaP management have been made through use of PSA to detect CaP earlier and improve outcome through earlier treatment, there has become (as discussed above) an over diagnosis of small-volume disease most of which is likely to be indolent based on historical CaP statistics. These men would otherwise die never knowing of the these small ineffectual tumor foci. Currently there are no biomarkers to differentiate indolence/aggressiveness CaP. We however have a grand opportunity to examine the extensive archives of CaP tissue in PAH that spans the time period that witnessed this change in clinical practice.
Finding Markers of Treatment Resistance — To date, most gene expression profiling data from patient samples has focused on gene expression and chromosomal differences and between tumor and normal samples, while a few studies have investigated late stage refractory CaP. Suffice it to say that when primary prostate tumors are treated by androgen ablation, androgen sensitive cells (which represent the majority of the tumor population) die, while remaining cells adapt to the androgen-deprived environment and eventually recur with a treatment-resistant phenotype. This response to treatment within subpopulations of tumor cells is the key to understanding therapeutic resistance and the development of rational molecular-based therapeutics. However, to experimentally identify these cells and the critical changes that underlie therapeutic resistance one must expression profile CaP samples after treatment stress as opposed to treatment-naive samples. In this regard we are uniquely poised to identify treatment-induced changes by profiling LCM samples from patients with high risk CaP that have undergone 6 months of NHT +/- docetaxel, prior to surgery. In preliminary data for gene expression profiling we have found that despite tumor heterogeneity there are many highly consistent alterations in gene expression in response to androgen ablation . We hypothesize that CaP cells surviving after treatment will reflect the emerging molecular phenotype that drives AI progression and therapeutic resistance.
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