The long term objective of these studies is to develop, characterize, and refine novel strategies to manipulate prostate specific gene expression in order to facilitate the establishment of transgenic mouse models and gene therapies for translational prostate cancer research. The rationale for these studies is that direct genetic manipulation of the prostate translates into transgenic models that hereditarily exhibit reproducible pathologies characteristic of human disease. These can be used simultaneously by investigators around the world to study the molecular basis of initiation, transformation and progress of prostate cancer. As well, these studies translate into the design of prostate-specific gene- based therapies that can be tested rapidly in tahe animal models. To this end, the principal investigator and his collaborators will continue development of a novel system based on the regulatory elements of the rat probasin (PB) gene shown during the term of the initial SPORE award to target developmentally and hormonally regulated heterologous gene expression, specifically to the prostate in transgenic mice. Lines of transgenic mice have already been established carrying either a PB-ras construct that reproducibly develop prostate hyperplasia or a PB-Tag construct that reproducibly develop prostate cancer. Having demonstrated that the murine prostate can be transformed as a consequence of targeted oncogene expression, it will be a primary objective of this project to thoroughly characterize the initiation, development and progression of prostate disease in these mice at the histologic, pathologic and molecular levels and establish PB-myc mice to compliment these models. Since the role of p53 in the development of prostate cancer metastases has been demonstrated using p53-deficient mice, a prostate-specific gene knock-out system based on the cre-lox recombinase strategy will be developed to facilitate further characterization of the loss of wild-type tumor suppressor genes and other genes identified through genetics studies to correlate with prostatic disease. This approach will also facilitate investigation into the role of the retinoblastoma (Rb) protein in the progression of prostate cancer since Rb-deficient mice are not sufficiently viable for these studies. In order to further facilitate translational research, the prostate-specific expression system will be used to generate a novel prostate-specific p53-based gene therapy strategy designed to exploit the p53-dependent apoptotic pathway for the treatment of prostate cancer. The efficacy of this strategy will be tested in the transgenic models. Therefore, the strategies designed to manipulate prostate-specific gene expression developed in this project will be used both to identify biological factors involved in the progression of prostate cancer and in the development and testing of innovative medical strategies for the prevention and treatment of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058204-08
Application #
6316544
Study Section
Project Start
2000-06-01
Project End
2002-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
8
Fiscal Year
2000
Total Cost
$174,672
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Olar, Adriana; He, Dandan; Florentin, Diego et al. (2014) Biological correlates of prostate cancer perineural invasion diameter. Hum Pathol 45:1365-9
Olar, Adriana; He, Dandan; Florentin, Diego et al. (2014) Biologic correlates and significance of axonogenesis in prostate cancer. Hum Pathol 45:1358-64
Sonpavde, Guru; Wang, Mingjun; Peterson, Leif E et al. (2014) HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer. Invest New Drugs 32:235-242
Nakka, Manjula; Agoulnik, Irina U; Weigel, Nancy L (2013) Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells. Int J Biochem Cell Biol 45:763-72
Ding, Yi; He, Dandan; Florentin, Diego et al. (2013) Semaphorin 4F as a critical regulator of neuroepithelial interactions and a biomarker of aggressive prostate cancer. Clin Cancer Res 19:6101-11
Feng, Shu; Dakhova, Olga; Creighton, Chad J et al. (2013) Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression. Cancer Res 73:2551-62
Yang, Feng; Zhang, Yongyou; Ressler, Steven J et al. (2013) FGFR1 is essential for prostate cancer progression and metastasis. Cancer Res 73:3716-24
Yang, Guang; Goltsov, Alexei A; Ren, Chengzhen et al. (2012) Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer. Mol Cancer Res 10:218-29
Sonpavde, Guru; Thompson, Timothy C; Jain, Rajul K et al. (2011) GLIPR1 tumor suppressor gene expressed by adenoviral vector as neoadjuvant intraprostatic injection for localized intermediate or high-risk prostate cancer preceding radical prostatectomy. Clin Cancer Res 17:7174-82
Wang, Jianghua; Cai, Yi; Shao, Long-Jiang et al. (2011) Activation of NF-{kappa}B by TMPRSS2/ERG Fusion Isoforms through Toll-Like Receptor-4. Cancer Res 71:1325-33

Showing the most recent 10 out of 262 publications