Date of Graduation
Masters of Science (MS)
Dr. Dean Tang
Dr. David Johnson
Dr. Mark McArthur
Dr. Taiping Chen
Dr. Donna Kusewitt
Prostate cancer (PCa) is one of the leading malignancies affecting men worldwide. Our lab focuses on understanding the molecular mechanisms underlying prostate carcinogenesis and developing therapeutics that target the cells responsible for driving PCa and mediating therapy resistance. My master thesis research employs a phage display library screening technology aiming to identify peptides that preferentially home in to undifferentiated PCa cells, which our lab has previously demonstrated to be intrinsically resistant to castration.
There is now evidence that a population of cells in PCa possesses characteristics associated with stem cells; these cells are referred to as cancer stem cells (CSCs). CSCs have been implicated in tumor propagation, progression and recurrence. In PCa, androgen deprivation therapy (ADT) is the mainstay treatment however, the majority of patients relapse after treatments, resulting in castration-resistant prostate cancer (CRPC). Our lab has provided evidence that the phenotypically undifferentiated PCa cell population expressing low levels or no prostate specific antigen (i.e., PSA-/lo) is enriched in prostate cancer stem cells (PCSCs) that can long-term propagate tumors and also resist ADT. The PSA-/lo PCa cell population represents the best characterized PCSCs and likely a cell-of-origin for CRPC. Consequently, it is important to find therapeutics that can preferentially target these cells. To this end, we employed highly purified PSA-/lo LNCaP PCa cells to perform phage display library screening. Our preliminary efforts identified two peptides, JRM1 and JRM2 that displayed preferential binding to PSA-/lo PCa cells.
We first identified a potential peptide that may home in to the PSA-/lo LNCaP cells by conducting a phage display library screening of LNCaP PSA-GFP utilizing a competitive assay technique. This peptide, TEWDYLTV, referred to as JRM1, showed slight but not statistically significant, preferential binding to the PSA-/lo LNCaP cells. With this knowledge we carried out another phage display library screening using adherent LNCaP PSA-GFP cells and an indirect subtraction assay. The results led to the identification of peptide JRM2, GFYVGQR, which demonstrated preferential and statistically significant binding to the PSA-/lo LNCaP cells. With this peptide we would like to attach either anti-cancer drugs or pro-apoptotic peptides to it and measure their effectiveness at killing undifferentiated and castration-resistant PCa cells.
Prostate cancer stem cells, PSA-, Phage Display, Peptides