): Prostate cancer is the second most common cause of death from cancer in U.S. men. Effective treatment of advanced disease demands a better understanding of prostate cancer tumor biology. Dr. Joel B. Nelson aspires to a career of independent research producing those insights which lead to useful therapy for prostate cancer. Therefore, the mutually inclusive objectives of this application are 1) to support the development of an outstanding clinician research scientist, and 2) to investigate the endothelin B receptor (ETB) as potential human prostate cancer tumor suppressor. This mentored research award will provide Dr. Joel B. Nelson with a vehicle for training in the molecular biology, signal transduction and receptor pharmacology of human prostate cancer at the Brady Urological Institute Research Laboratories of the Johns Hopkins University School of Medicine, under Dr. William G. Nelson, the award sponsor. The predominant endothelin receptor on benign prostate epithelial cells, ETB is greatly reduced in prostate cancer and is associated with somatic hypermethylation of CpG dinucleotide sequences in the 5' region of the ETB gene in over 60% of the prostate cancers studied. The ETB receptor has unique functions, including ligand clearance, inhibition of endothelin-1 secretion, and activation of counterregulatory pathways. This project is designed to investigate the hypothesis that loss of ETB function in prostate cancer directly contributes to carcinogenesis, progression and morbidity. To test the hypothesis that loss of ETB expression is a critical step in prostate carcinogenesis, ETB expression will be reconstituted in prostatic carcinoma cell lines via stable transfection of ETB-encoding cDNA constructs. ETB expressing subclones will be assessed for growth potential, tumorigenicity, and phenotypic selection. To test the hypothesis that loss of ETB expression in prostate cancer causes local ET axis deregulation, the regulation of ET-1 expression and production in prostatic cell lines which express the ETB receptor will be studied. To test the hypothesis that loss of ETB expression results in the loss of critical ETB mediated secondary messenger pathways, several signaling cascades will be studied in both normal and malignant prostate tissues. To test the hypothesis that loss of ETB expression can result from ETB gene mutations, determination of ETB mRNA expression by in situ hybridization will be coupled with ETB mutation analysis. The broad approach to this evolving question in prostate cancer tumor biology will provide an excellent training experience and novel insights.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA074090-02
Application #
2700740
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
1997-05-01
Project End
2002-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Urology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Pflug, Beth R; Zheng, Hong; Udan, Michael S et al. (2007) Endothelin-1 promotes cell survival in renal cell carcinoma through the ET(A) receptor. Cancer Lett 246:139-48
Carducci, Michael A; Nelson, Joel B; Bowling, M Kathy et al. (2002) Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol 20:2171-80
Ackerstaff, E; Pflug, B R; Nelson, J B et al. (2001) Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res 61:3599-603
Pizer, E S; Pflug, B R; Bova, G S et al. (2001) Increased fatty acid synthase as a therapeutic target in androgen-independent prostate cancer progression. Prostate 47:102-10
Pflug, B R; Reiter, R E; Nelson, J B (1999) Caveolin expression is decreased following androgen deprivation in human prostate cancer cell lines. Prostate 40:269-73