Every three minutes an American male is diagnosed with prostate cancer and every hour 4 men die of this disease. Because of the poor prognosis for men with metastatic (i.e., non-organ-confined) prostate cancer, efforts to control this disease have focused on aggressive screening to detect cancer while localized and potentially curable. The complication of such screening is the prevalence of histologic cancers in the population. Unfortunately, if diagnosed when non- organ-confined, prostate cancer is a fatal disease for which there is no curative therapy. It is estimated that aggressive screening could identify 10 million men with histologic cancer. At this time it is not possible to identify which histologically localized cancers will complete malignant progression and, therefore, require aggressive therapy as opposed to those which are truly indolent, possibly requiring only conservative therapy. It is thus impossible to distinguish patients with histologic prostate cancer requiring no therapy from those requiring local therapy or local therapy with systemic therapy. Delineation of the cellular and molecular pathway(s) of metastatic progression may provide markers useful in substaging individual tumors and predicting the clinical course of prostate cancer. To these ends the goal of Dr. Rinker-Schaeffer's laboratory is to identify molecular and cellular changes associated with the metastatic progression of prostate cancer for use in the clinical substaging. Although multiple genetic changes have been associated with metastatic progression, activation of oncogenes and loss of tumor suppressor genes appear to be associated with, but not sufficient for, the acquisition of metastatic ability. In contrast, loss of putative metastasis- suppressor genes would allow primary tumor cells to become metastatic. Metastasis-suppressor genes encode products that normally function to suppress metastasis. Dr. Rinker-Schaeffer's proposed research employs molecular and cellular approaches to identify metastasis-suppressor genes for prostate cancer. Genes which normally function to suppress prostate cancer metastasis will be identified by transferring human chromosomes into highly metastatic rat prostatic cancer cells and assaying for metastasis suppression in vivo. Clinically, chromosome 17 is a logical candidate for these studies since its loss has been associated with prostate cancers, and the metastasis-suppressor gene nm23 has been mapped to 17q21.3. In addition, Brothman et al have recently reported LOH on chromosome 17 in a region near, but distinct from, the familial breast cancer gene (BRCA1) at 17q21. Initial studies demonstrate that chromosome 17 encodes a gene(s) which specifically suppresses metastatic ability of prostate cancer cells. Interestingly, these studies found no apparent correlation between the level of p53 and nm23 proteins and metastasis suppression, suggesting chromosome 17 encodes additional metastasis-suppressor activities. The studies proposed in this grant use these preliminary findings as a basis for identification of metastasis-suppressor activities encoded by chromosome 17. A strategy is to use functional and localization studies to identify candidate genes which: 1) map to the metastasis-suppressor region and 2) have a biological function which suggests a role in metastasis suppression. These candidate genes will then be transfected into prostate cancer cells and tested for their ability to suppress spontaneous metastasis. Once identified, the metastasis-suppressor genes will be tested for their ability to accurately substage clinical prostatic cancer samples.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA069487-04
Application #
2871880
Study Section
Pathology B Study Section (PTHB)
Program Officer
Berman, Jules J
Project Start
1996-02-13
Project End
2001-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Rinker-Schaeffer, C W; Welch, D R; Sokoloff, M (2000) Defining the biologic role of genes that regulate prostate cancer metastasis. Curr Opin Urol 10:397-401
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