DHSA Pilot Projects:
Project Title: "Androgen Receptor and Prostate Cancer"
Co-Investigators: Robert Sikes, UD, Karen Knudsen, TJU, Ayyappan Rajasekaran, Nemours, and Charles Schneider, Christiana Care.
Background and Significance:
Initially, prostate cancer is sensitive to the levels of male steroid hormones or androgens. Removal of the androgens (Male Sex Hormones), by surgical or chemical castration, is still a gold standard for prostate cancer therapy. For a time, the cancer responds by regressing under the conditions of androgen deprivation. However, the cancer invariably adapts and continues growing in the absence of androgens or in the presence of reduced levels of androgens. The cancer then shifts from being androgen dependent or sensitive to an androgen insensitive state. The term now being used is, castration-resistant prostate cancer or CRPC. The development of metastases, along with the shift from androgen sensitive to androgen insensitive is termed progression. Despite the importance of understanding androgen action in the prostate, little is understood about the mechanisms underlying androgen dependence, and the means by which the androgen requirement is bypassed in relapsed tumors. This project is concerned with the mechanism(s) that contribute to the development of advanced and castration-resistant prostate cancer as defined above and delineating the molecular mechanisms that govern these events. The project will also evaluate combined androgen blockade therapy to convert RT-PCR detection of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts from positive to negative in the peripheral blood of patients with clinically localized prostate cancer and in animal xenograft models with and without castration.
Knowledge gained from these studies could potentially increase biochemical failure-free survival after curative therapy for patients with prostate cancer. It is also important to note that the next major cancer screening project in Delaware by the Delaware Cancer Consortium will be for prostate cancer.
Specific Aims:
The goal of this proposal is to build up translational research program studying biological significance of JAM-A and its relationship to post-MI complications. The proposal includes three goals.
- Aim 1: Influence of bone marrow stromal (BMS) cells on the establishment of PCa in the bone microenvironment and development of CRPC.
- Aim 2: Elucidating the role of PSMA in CRPC.
- Aim 3: Determine the influence of cell cycle aberrations on AR signaling and CRPC growth in the bone microenvironment.