Date of Award

Winter 2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

Richard Drake

Committee Member

Neel Krishna

Committee Member

Julius Nyalwidhe

Committee Member

O. John Semmes

Abstract

Presently, prostate cancer is the most common cancer afflicting men in the United States, with serum PSA being the "gold standard" protein biomarker used in the clinic for detecting and diagnosing prostate cancer. Nonetheless, serum PSA levels can also be elevated in non-cancerous conditions as well, such as benign prostatic hyperplasia (BPH). Due to this overlap, many unnecessary biopsies and radical prostatectomies occur, leading to patient distress. Despite recent advances to clinical assays which consider other clinical parameters, there is still a great need for improved clinical detection methodologies for prostate cancer, including improved biomarkers. Therefore, this research project aims to examine the N-glycosylation patterns of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) in prostate proximal fluids, as well as to examine the total glycan profile for prostate proximal fluids with the intent of discovering carbohydrate-based biomarkers for the detection of early prostate carcinomas. To this end, preliminary glycomic and proteomic studies were completed using seminal plasma samples, based on the disease cohorts normal, BPH, and prostate cancer. These samples resulted in sufficient protein levels of both PSA and PAP for glycopeptide and glycomic analyses. Furthermore, these studies led to additional knowledge of PSA and PAP glycosylation. In addition to this sample set, pools of disease-defined expressed prostatic secretions (EPS) were generated and subsequently analyzed for detection of both protein levels and carbohydrate structures of PSA and PAP, as well as examined for their total glycomic profile. We succeeded in characterizing EPS fluids for both protein and carbohydrate content, as well as identified potential carbohydrate targets for the generation of new clinical assays for the detection of early prostate carcinomas. These targets are fucosylated, complex sub-type glycans which we found to be under-expressed in prostate carcinoma samples as compared to their non-cancerous counterparts. We believe EPS fluids have utility not only for discovery of cancer biomarkers, but also for use in future clinical assays.

Comments

A Dissertation Submitted to the Faculty of Eastern Virginia Medical School and Old Dominion University in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/44gs-cd38

ISBN

9781109719925

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