Prostate cancer (CaP) metastases, especially to bone, are the cause of significant morbidity and mortality. Since all metastases emanate from disseminated tumor cells (DTC), the study of DTC is critical to our understanding of the metastatic process and the design of novel therapeutic strategies. In the past, the field has generally focused on the detection of these shed cells in the circulation or in bone marrow. We have recently turned our attention to the characterization of DTC which is imperative for further insight. We hypothesize that specific genomic and/or gene expression profiles of the DTC will be prognostic for both biochemical failure post radical prostatectomy and duration of response to androgen ablation. Also, we predict significant differences will be observed between these DTC profiles and those of the primary tumor. We also hypothesize that some of the DTC have cancer stem cell attributes while others isolated from patients who have no evidence of disease (NED) after surgery have attributes of dormant tumor cells.
Our Specific Aims are as follows:
Aim #1 : Detect, isolate and characterize the DTC from patients pre-radical prostatectomy who are at high risk (Gleason sum >6) of recurrence and correlate to outcome and profiles of the primary tumor.
Aim #2 : Detect, isolate and characterize the DTC from patients undergoing androgen ablation with comparison of profiles to that of bone and non-bone metastases.
Aim #3 : Define the biological functionality of DTC with regard to stem cell attributes, tumor cell dormancy and markers associated with bone metastases such as IGF-IR, RUNX2, and TMPRSS2-ERG gene fusions. The successful execution of these three aims will provide considerable insight on the biological character of the DTC in CaP. It may also provide a mechanism whereby the genomic profile of the DTC detected (a) eariy in disease may be predictive of recurrence and (b) late in disease may be predictive of the duration of response to androgen ablation. Finally, one of the most exciting aspects is our quest to determine if in some instances these DTC mimic cancer stem cells while in others they portray tumor cell dormancy.
Since all metastases emanate from disseminated tumor cells (DTC), the study of DTC is critical to our understanding of the metastatic process. The biological and molecular character of these cells is largely unknown due to challenges in isolation and the very few cells obtained for study. We've made significant advances in this area and are prepared to explore potential attributes such as stem-cellness and dormancy.
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