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Prostate Program
Program Leaders: James L. Mohler, MD and Gary J. Smith, PhD
| Contact Person: | Marie Rosati, Prostate Program Telephone: 716-845-4155 Fax: 716-845-4165 marie.rosati@roswellpark.org |
Goals and Themes
The overall goal of the Prostate Program is to develop and test new approaches for the diagnosis and treatment of prostate cancer by facilitating interactions between scientists and clinician-scientists. This goal is being pursued through multiple interrelated approaches, including:
(a) evaluation of androgen synthesis within prostate cancer cells;
(b) identification of alternative mechanisms of regulation of AR-mediated transcription;
(c) characterization of prostate stem cells;
(d) description of the response of the vasculature to therapy;
(e) evaluation of Vitamin D and selenium as therapeutic agents in prostate cancer; and
(f) identification of new diagnostic and prognostic biomarkers.
The research interests of the membership of the Prostate Cancer Program are distributed among five highly interactive research themes: racial differences, androgen receptor, tumor microenvironment, Vitamin D and Selenium, and biomarkers.
The Racial Differences theme is addressed through the Department of Defense funded Consortium, Prostate Cancer Project (PCaP, James Mohler, MD). PCaP seeks to identify the relative contribution of: (1) interaction with the healthcare system; (2) host biology; and (3) tumor biology to racial differences in prostate cancer mortality. Research subjects with newly-diagnosed prostate cancer, 1000 from North Carolina of whom 500 are African American and 500 are Caucasian, and 1000 from Louisiana of whom 500 are African American and 500 are Caucasian, are identified using rapid case ascertainment. African Americans in North Carolina have one of the highest, and African Americans in Louisiana have one of the lowest, mortality rates from prostate cancer in the US while Caucasian Americans in the two states have similar prostate cancer mortality and it is less than that in either African-American group. In-home visits include an extensive diet and health care survey and collection of blood (serum, plasma DNA and immortalized WBCs), adipose tissue, toe nail specimens and urine for evaluation of diet and host biology. Tissue sections and microarrays are produced from diagnostic prostate biopsies and radical prostatectomy specimens respectively to evaluate tumor biology. Of a total of nine projects, two projects that focus on the androgen axis (Dr. Mohler) and prostate stem cells (Gary Smith, PhD) are sited at RPCI.
The Androgen Receptor theme focuses on understanding the mechanism of androgen receptor (AR) function in the absence of circulating testicular androgens in men treated with androgen deprivation therapy for advanced prostate cancer. Projects are focused on multiple aspects of this problem, including:
- AR activation by intracrine production of androgens in recurrent prostate cancer (Dr. Mohler);
- AR activation by stromally derived co-regulators in the androgen deprived microenvironment (Sergio Onate, PhD);
- AR regulation by cytokine signaling in recurrent prostate cancer (Allan Gao, MD, PhD);
AR regulation by selenium (Dr. Gao); and - AR regulation by breast cancer resistance protein (BCRP) in prostate stem cells (Dr. Smith and Wendy Huss, PhD).
The Tumor Microenvironment theme focuses on stromal-epithelial interaction, tumor vasculature, and the bone microenvironment in prostate cancer metastases. Projects are focused on vascular homeostasis and angiogenesis in prostate cancer (Dr. Smith) and kidney cancer (Kenneth Gross, PhD; Hyung Kim, MD). Identification of unique therapeutic targets is a major emphasis of vascular studies in both tumor models. Destabilization of the vasculature by androgen deprivation therapy or chemotherapeutic regimens perturbs the signaling milieu within the tumor affecting tumor cell survival. Drs. Wang and Kim, new members of the CCSG and Prostate Program, received their experimental training in the laboratory of John Subjeck, PhD (CSBT) and continue Inter-Programmatic collaborations with Dr.Subjeck (CSBT) and Elizabeth Repasky, PhD (TII). During their training, Drs. Wang and Kim participated in many of the seminal studies that led to the development of the tumor vaccine models discussed in the Cell Stress and Biophysical Therapy Program. Identification of those unique molecules may also provide targets for development of immunotherapeutic approaches (Xiang-Yang Wang, PhD). In addition, PSA appears to have antiangiogenic effects (Kailash Chadha, PhD). The preference of prostate cancers for bone as a site for metastasis is studied using TRAMP cell lines that produce blastic bone lesions (Barbara Foster, PhD) and analysis of the growth enhancing effect of osteoblasts on prostate cancer cells (Dr. Gao).
The Selenium and Vitamin D theme focuses on their use for chemoprevention and to enhance the safety and effect of chemotherapy. Selenium reduces AR activation and expression of PSA in LNCaP cells (Dr. Gao). Vitamin D is a therapeutic agent and a potentiator of taxane and other antitumor agents (Candace Johnson, PhD). Vitamin D treatment induces apoptosis and cell cycle arrest, and down-regulates P-MAPK, P-Akt, p53 and MEK-cleavage. Inhibition of calcitriol catabolism in vivo by the CYP24 inhibitor ketoconazole enhances the antitumor activity of calcitriol. In the TRAMP mouse, calcitriol decreases tumor burden in intact mice, but does not prevent androgen independent disease (Dr. Foster). Vitamin D promotes differentiation, induces cell cycle arrest, growth inhibition and apoptosis, and is anti-angiogenic.
The BioMarkers of prostate cancer theme focuses on PSA for early detection and proteomic analysis of serum for prognosis. Current diagnostic technologies for PSA detection are based on immuno-detection of the protein portion of the molecule. However, post-translationally modified derivatives of PSA may provide unique and specific diagnostic markers (Khushi Matta, PhD). The biology of PSA continues to be investigated; PSA down-regulates expression of the pro-angiogenic growth factors, VEGF, Pim-1 oncogene and uPA, and up-regulates interferon, modulates protein expression in PC-3M cells and suppresses prostate tumor growth in nude mice (Dr. Chadha). Proteomic analysis of serum from PCaP research subjects may identify biomarkers associated with the aggressive phenotype of prostate cancer (Dr. Mohler).
Program Members
Related link: North Carolina - Louisiana Prostate Cancer Project (PCaP)
