This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer is the most common cancer diagnosed in the United States and accounts for about 30% of cancer incidence and 12% of cancer mortality among men. The high prevalence rate and the long latent period between the cancer-initiating events and the development of invasive disease makes prostate cancer a prime candidate for chemoprevention. The etiology of prostate cancer is incompletely understood, but familial factors probably play a significant role. Recent data suggest that heredity may play a role in 20-25% of early age onset prostate cancer. Extensive investigations have demonstrated that polyamine regulation is important in cellular proliferation and carcinogenesis. Recent studies indicate that polyamines may affect the expression of genes involved in tumor invasion, including genes involved in prostate cancer. These and other experimental data provide a rationale for depletion of tissue polyamine content as a strategy for chemoprevention of prostate malignancy. We propose a population-based project to study etiologic factors of prostate cancer which will integrate (a) inherited susceptibility gene(s); (b) genetic alterations; and (3) epidemiologic risk factors including family history and environmental exposures. In the event that a major prostate cancer susceptibility gene is cloned during the course of this study, we will test the sample for mutations in that gene. This will be done in order to determine the frequency distribution and penetrance of that gene in the population. Epidemiologic risk factor information will be used to determine whether the expression of susceptibility genes or other genetic alterations may be modified by environmental factors. The major hypothesis to be tested in this project is to determine whether alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (OCD, the key enzyme on the pathway to polyamine synthesis), can suppress tissue polyamine content and progression-related genes in prostate tissue of individuals at high genetic risk for prostate cancer. The primary endpoints will be the polyamines, putrescine, spermidine, and spermine which are essential for optimal cell proliferation. Our group has had extensive experience with DFMO as a prevention and therapeutic agent.
The specific aims of this updated protocol Project II of PPG are: 1. To conduct a randomized placebo-controlled phase IIb trial of DFMO in brothers and first-cousin males of probands with a familial history of early age onset prostate cancer. Probands will be below age 70. Participants in the clinical trial will be brothers or male first degree cousins of the proband and below age 70 and 35 years or older at time of study entry. Participants will not have any limiting chronic disease that would project less than a 5-year survival or would preclude prostate biopsy. Serum total and free PSA as well as a prostate ultrasound with volume measurements will also be done. Sextant needle biopsies of the prostate gland will be performed, histopathologic evaluation made, and polyamine content and surrogate intermediate biomarkers (SEBs) measured (Project II). This project will also attempt to look for and to identify possible genetic links and their interactions with environmental exposures and other risk factors reported to be associated with prostate cancer. Participants will be randomized into equal-sized groups taking placebo or 500 mg per day of DFMO and carefully monitored for side effects, including audiologic changes. After one year, sextant biopsies will again be done and laboratory parameters measured, as above. 2. To carefully assess the side effects of DFMO in this population and to compare them to the biological effect on the prostate gland. Results from the clinical trial and from Project II will be analyzed. Optimally, we will be able to determine the dose at which polyamine content is suppressed and SEB changed without clinical side effects being produced. We have successfully accomplished such a goal in individuals at high risk for colon cancer. Additionally, we will determine the frequency distribution and penetrance of genetic alterations or susceptibility genes in the population and investigate possible interactions between prostate cancer susceptibility genes or genetic alterations and environmental factors and their relationship to cancer risk.
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