The NIA singled out prostate cancer as one of the first extramural research initiatives developed by its Cancer Section, newly created in 1996, in the NIA Geriatrics Program. According to the NCI SEER Program, prostate cancer is a disease of older men, with 77 percent of all prostate cancer cases and 92 percent of prostate cancer mortality occurring in the 65+ age group. Prostate cancer also has the highest incidence of any malignancy for white and black men 65 years and older, 1186.5 and 1593.7 per 100,000 population, respectively. In addition, age-adjusted mortality rates are more than twice as high for African Americans as for white Americans. Guided by these facts, the NIA issued a Program Announcement, "Aging, Race, and Ethnicity in Prostate Cancer" (PA-97-019) in the NIH Guide to Grants and Contracts (Volume 25, Number 44). This PA encourages the extramural research community to take advantage of recently acquired scientific knowledge and expertise developed in biology, gerontology, oncology, urology, and other disciplines and professions, as well as to apply these resources to aging-relevant research questions on prostate cancer for aging males of different races and minority backgrounds. The clinical component of this PA encourages studies on determinants of age- and race-associated differences in prostate cancer detection, treatment, and survival. Other major components of the PA solicit studies on the etiology and risk factors that affect the rate of increase with age in prostate cancer and on developing new methods and testing improved methods to identify high risk older white and African American men and low risk men of different racial and ethnic origins.
The NIA's intramural program has used its unique resource, the Baltimore Longitudinal Study of Aging (BLSA), to investigate the longitudinal trends in prostate specific antigen (PSA). The BLSA investigates how these trends influence the utility of this measure in detecting prostate cancer, in prospectively identifying men at high risk for the disease, and in determining the prognostic and diagnostic value of the free/total ratio of PSA. NIA investigators have also examined the linkage between longitudinal testosterone levels, insulin-like growth factors (IGF-I and IGF-II, and IGF binding protein-3), and prostate cancer risk.
Research from the BLSA continues to study the time course for the development of prostate cancer and markers useful in early diagnosis. The goal is to define which groups of men should be tested, how long and how often they should be tested to maximize the identification of treatable prostate cancer while minimizing the costs of evaluation. This work has shown that the rate of change in prostate specific antigen over time, known as PSA velocity, improves the specificity of PSA. This means that knowing how fast PSA levels change over time allows identification of men at higher risk for the development of prostate cancer. In these studies, 70 percent of men ultimately diagnosed with prostate cancer had a PSA velocity exceeding 0.75 ng/ml per year. Less than five percent of men without prostate cancer have a rate of change in PSA exceeding 0.75 ng/ml per year. These data have now been confirmed in large prospective screening trials. Investigators have also shown that a PSA screening frequency of two years is not likely to miss a curable prostate cancer when the initial PSA level is less than two ng/ml, thus reducing the required frequency for PSA screening in many men.
Recently, free/total PSA ratio has become available for clinical use. Low ratios have been shown to be associated with prostate cancers. Studies of men in the BLSA have now shown that the free/total PSA ratio was abnormally low 10 years prior to diagnosis in the cohort of subjects who ultimately were diagnosed with prostate cancer. Therefore, by using the PSA free/total ratio it is possible to identify men at risk even when total PSA values are within normal limits as was the case in the BLSA cohort. Further correlations of these data show that the percentage of free prostate-specific antigen in sera predicts aggressiveness of prostate cancer before diagnosis. These findings can improve the ability to screen men for this disease and make it possible to identify men who are at higher risk of developing an aggressive cancer. By knowing early that a cancer is present, and by knowing its aggressiveness, men and their physicians can better plan appropriate therapeutic strategies.
NIA and Johns Hopkins University School of Medicine investigators have used the BLSA cohort to examine the role of hormones in promoting prostate cancer as well as the potential use of hormone measurements as potential markers of prostate cancer risk. These studies have employed a "retro-prospective" study design, using stored samples from the BLSA collection taken as much as 15 years before men developed clinical evidence of prostate cancer and comparing them with samples from age-matched men followed for similar periods of time with no diagnosis of prostate cancer. To date, these studies have provided evidence that serum testosterone levels, whether measured as total or biologically available fraction, do not predict subsequent development of prostate cancer.
Previous studies evaluating the roles of circulating insulin-like growth factors (IGF-I and IGF-II) and their major plasma binding protein, IGF binding protein-3 (IGFBP-3), have suggested that lower than average levels of IGF-I and high levels of IGF-II may each be independently associated with a reduced risk of prostate cancer, while the apparent protective effect of IGFBP-3 was not statistically significant. In contrast, recent NIA intramural studies have shown that once levels of PSA are known, determinations of IGF-I, IGF-II, and/or IGFBP-3 add no useful predictive information for identifying patients at high risk for prostate disease in groups of longitudinally-followed middle aged and older men. Further studies are planned to investigate the role of longitudinal changes in growth factors and sex steroids in predicting prostate cancer risk.
National Institute of Nursing Research
Care of Men with Prostate Cancer:
NINR has identified opportunities for expanding its biobehavioral and psychosocial research on prostate cancer to include:
managing symptoms following treatment (e.g., urinary incontinence and pain);
nursing interventions to improve quality of life, including sexual role and function;
decision-making associated with treatment options (e.g. watchful waiting vs. surgery);
decision-making associated with screening for prostate cancer.
These studies would provide important knowledge to improve decision-making, management of symptoms, and quality of life for men with prostate cancer.
National Institute of Mental Health
NIMH supports research on the interactions of stress and emotions with life-threatening illnesses such as cancer. A primary focus of NIMH-supported research related to prostate cancer is characterization of the stress of with having prostate cancer and undergoing a radical prostatectomy. This research examines psychological, physiological, and quality-of-life changes associated with the surgery and short- and long-term recovery; it also examines dispositional and environmental factors that might serve to predict response to surgery and long-term recovery. An objective of this research is to develop a pre-surgical stress management approach that will reduce the negative impact of prostatectomy on patients. Other NIMH research explores the genetic basis of familial prostate cancer.
National Institute of Deafness and Other Communication Disorders
Mammalian bombesin receptors are expressed by some prostate tumor cells, and can mediate a bombesin-dependent growth stimulatory response in some prostate carcinoma cell lines. In this project, the structure, function, and regulation of three mammalian bombesin receptor subtypes is defined at the molecular level. Recent studies have: 1 ) identified structural determinants essential for binding both agonist and antagonists; 2) established that agonist-mediated receptor phosphorylation occurs within seconds after ligand binding, and attenuates receptor signaling and interaction with cognate GTP-binding proteins; and 3) created mouse models unable to express two of the known mammalian bombesin receptors, both of which show abnormalities in weight control and/or satiety. A more complete understanding of bombesin receptor function would hopefully facilitate the development of therapeutic strategies that utilize bombesin receptors as therapeutic targets in the diagnosis and treatment of human prostate cancer.