The dual purpose of this application is to request support for the training of G. Steven Bova M.D. as a medical scientist, and to advance understanding of the molecular events leading to the development of prostate Cancer. Dr. Bova seeks to build upon his background as pathologist and urologic surgeon to become an independent investigator in the basic science of urologic oncology. This research training would take place under the sponsorship of William B. Isaacs Ph.D., in the setting of the Brady Urologic Institute of The Johns Hopkins University School of Medicine. Despite the magnitude of the medical problem which prostate cancer constitutes, a basic understanding of the molecular events responsible for the initiation and progression of this disease remains elusive. The primary research goal of Dr. Isaacs' laboratory is to identify and clone the genes which, as a result of genetic alteration, are responsible for human prostate carcinogenesis. To this end, a systematic approach utilizing molecular and cell biology techniques has been initiated to analyze molecular genetic aspects of human prostate cancer. Preliminary studies by Dr. Bova and others have demonstrated frequent loss of genetic material from chromosomes 8p, 10, 16q, and 17p, suggesting that genes important in the development of prostate cancer are located in these regions.
Specific aim 1 is to test the hypothesis that tumor suppressor genes reside in these deleted chromosomal regions by introducing normal chromosomes 8, 10, 16, 17 and others into human prostate cancer cells via microcell transfer. Tumorigenicity of hybrid cells will be assayed by injection in nude mice. Motility and invasive potential of hybrid cells will be assayed by time-lapse videomicroscopy, complemented by in vitro assays of extracellular matrix invasion. The presence and degree of intactness of transferred chromosomes will be determined by a combination of molecular and cytogenetic techniques, including Southern blotting, PCR analysis, and in situ hybridization.
Specific aim 2 is to provide a base for positional cloning efforts by identifying subchromosomal regions capable of suppressing the tumorigenic phenotype by comparing the effect of transfer of intact and partially deleted chromosomes into wild type cells. These studies will provide the first functional evidence for the existence and location of tumor suppressor genes which become inactivated in human prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Physician Scientist Award (K11)
Project #
5K11CA059457-02
Application #
2100055
Study Section
Cancer Institutional Fellowship Review Committee (CT)
Project Start
1994-03-09
Project End
1999-02-28
Budget Start
1995-03-01
Budget End
1996-02-29
Support Year
2
Fiscal Year
1995
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
Kibel, A S; Christopher, M; Faith, D A et al. (2001) Methylation and mutational analysis of p27(kip1) in prostate carcinoma. Prostate 48:248-53
Kibel, A S; Freije, D; Isaacs, W B et al. (1999) Deletion mapping at 12p12-13 in metastatic prostate cancer. Genes Chromosomes Cancer 25:270-6
Kibel, A S; Isaacs, S D; Isaacs, W B et al. (1998) Vitamin D receptor polymorphisms and lethal prostate cancer. J Urol 160:1405-9
Bova, G S; Partin, A W; Isaacs, S D et al. (1998) Biological aggressiveness of hereditary prostate cancer: long-term evaluation following radical prostatectomy. J Urol 160:660-3
Kibel, A S; Schutte, M; Kern, S E et al. (1998) Identification of 12p as a region of frequent deletion in advanced prostate cancer. Cancer Res 58:5652-5
Bookstein, R; Bova, G S; MacGrogan, D et al. (1997) Tumour-suppressor genes in prostatic oncogenesis: a positional approach. Br J Urol 79 Suppl 1:28-36
Bova, G S; MacGrogan, D; Levy, A et al. (1996) Physical mapping of chromosome 8p22 markers and their homozygous deletion in a metastatic prostate cancer. Genomics 35:46-54
Bova, G S; Isaacs, W B (1996) Review of allelic loss and gain in prostate cancer. World J Urol 14:338-46
Jarrard, D F; Bova, G S; Isaacs, W B (1996) DNA methylation, molecular genetic, and linkage studies in prostate cancer. Prostate Suppl 6:36-44
Cher, M L; Bova, G S; Moore, D H et al. (1996) Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res 56:3091-102

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