Program Leader Eric J. Small, MD Program Co-Leader Marc A. Shuman, MD

UCSF clinical care for prostate cancer >

The Prostate Cancer Program comprises approximately 30 scientists from several disciplines who work together on the epidemiology, prevention, diagnosis, and treatment of prostate cancer. Programmatic research is focused on six broad themes, as described below.

Program research is supported additionally by a Specialized Program Of Research Excellence (SPORE) in Prostate Cancer grant, awarded in 2001 by the National Cancer Institute.

Steroid Receptors in Prostate Carcinogenesis, Progression, and Treatment
Little is known about the regulation of growth and differentiation of the prostate. Thus, it is important to investigate both normal processes and the transformation of normal epithelium to prostatic intraepithelial neoplasia, invasive prostate cancer, and finally metastatic prostate cancer. Understanding these linked processes will come from answers to questions such as: How is prostate differentiation regulated? Which are the androgen-regulated genes that control these processes? How does the androgen receptor (AR) activate these genes and what are the growth-stimulating pathways in hormone refractory prostate cancer? As program investigators answer such questions, they are exploiting insights for new avenues of therapeutic investigation. For example, small-molecule inhibitors of AR-regulated transcription are being developed, which are expected to compete with proteins that AR requires in its role as an assembly scaffold in controlling transcriptional activation of its target genes. It is hoped that this research will result in new types of drugs that inhibit prostate cancer in which AR remains active in spite of blockade of ligand binding. Other investigators are studying how the AR alters its ligand specificity during progression of hormone-independent disease. They are also characterizing genes associated with hormone-independent prostate cancer. Complementary to these studies on the mechanics of AR signaling are efforts to characterize genes involved in prostate cancer progression utilizing microarray technology.

Genetic Abnormalities Predisposing to Prostate Cancer and Promoting Prostate Cancer Progression
An important initiative focuses on characterizing mouse genetic loci that affect the survival time of transgenic mice with prostate cancer (TRAMP mice), and also on identifying mouse genetic loci that affect prostate tumor angiogenesis, tumor number, and/or tumor grade. Additionally, these investigators are carrying out a comparative analysis of somatic genetic alterations and gene expression changes in mouse and human prostate cancers to identify specific genetic markers of increased risk. Future studies will focus on exploiting candidate genes that emerge from the mapping studies of mouse prostate cancer resistance or susceptibility loci to identify human homologues and evaluate their roles in human prostate cancer susceptibility. Another group of investigators is hoping to identify genetic markers that will enable prediction of patient outcome and stratification of patients at intermediate risk of progressing into groups that should be treated with standard or experimental therapies. An informatics group is developing and deploying data analysis and visualization methods to support these efforts.

Novel Immunotherapeutic Approaches to Prostate Cancer
One pre-clinical investigation involving the TRAMP model has led to the discovery of a prostate antigen, SPAS-1, that is identified by T-cells activated by anti-CTLA4 antibodies. A human homolog to the novel SPAS-1 murine gene , which has been identified with 96 percent identity at the amino acid level, is highly expressed in human prostate cancer as well as some other human malignancies. The group plans to evaluate the efficacy of CTLA-4 blockade and immunization with prostate-related proteins in induction of autoimmune prostatitis and in rejection of TRAMP tumors in mice. Another investigator is developing recombinant antibodies that are prostate-specific, and hoping to identify both therapeutic recombinant antibodies and the antigens bound by these antibodies.

Proteases Critical for Prostate Cancer Progression
A number of investigators are studying the role of proteases in the progression of mouse and human prostate cancer. Types of proteases under investigation include the membrane-type serine protease (MT-SP) family; metalloproteases, including MMP-9, MMP-2, MMP-3, and MMP-13; cysteine proteases; and others. As one example, single-chain monoclonal antibodies that have been isolated from a phage display combinatorial library will be used to test the effect of selective inhibition of MT-SP1, which has been implicated in prostate cancer progression; the project aims to identify other closely related cancer-associated serine proteases and develop a potential anti-MT-SP1 therapeutic reagent. Other investigators are using transgenic models for the development and progression of mouse tumors in order to characterize the nature of protease involvement in transformation of epithelial cells as well as primary tumor growth, invasion, and metastasis. With these models, it is possible to determine the actions of specific proteases or classes of proteases, with the goal of elucidating their impact on all aspects of progression, from proliferation and apoptosis to influx of inflammatory cells, stromal activation, angiogenesis, matrix remodeling, malignant conversion, malignant grade, and metastasis. These model systems will provide proof-of-concept for anti-protease therapy in different stages of the development and progression of epithelial cancers.

Experimental Therapeutics
Among many efforts of Prostate Cancer Program investigators in the area of experimental therapeutics are: developing a mouse model for studying mutant adenoviruses for the treatment of prostate cancer; the development of therapeutic mutant telomerase genes that inhibit the growth of human prostate cancer cell lines when introduced by retroviral or lente viral constructs; combinatorial drug design of protease inhibitors, accomplished by developing computational procedures that add chemically relevant fragments to a scaffold; and Magnetic Resonance Imaging (MRI) and spectroscopy (MRS) techniques to aid in defining the presence, extent, and aggressiveness (grade) of prostate cancer and to provide an early means of determining therapeutic success.

Epidemiologic Research on Identifying Lifestyle Risk Factors for Prostate Cancer Recurrence
A new and important area of research is focused on dietary and lifestyle predictors of prostate cancer recurrence, progression, and mortality. In one study, men treated for prostate cancer will be followed annually for recurrence, progression, and mortality outcomes, and associations with dietary and lifestyle habits will be examined. Potential dietary and lifestyle risk factors for prostate cancer progression to be studied are focused on those that have been more strongly linked to advanced, metastatic, or fatal prostate cancer. Of primary interest in this cohort are fat and meat dietary content; dairy, calcium, and Vitamin D; vegetables; lycopene/tomato products; Vitamin E; and smoking. Serum and tissue prognostic factors will also be examined in conjunction with exogenous dietary/lifestyle risk factors. These serum/tissue prognostic factors include sex hormones, insulin-like growth factor-I (IGF-I), vitamin D, carotenoids, selenium, and vitamin E. Several lines of experimental and physiologic evidence support a role for sex hormones as initiators or promoters of prostate cancer, and a few prospective studies suggest that a high plasma testosterone:dihydrotestosterone ratio, high circulating levels of testosterone, low estrogen levels, or low levels of sex-hormone binding globulin may be associated with moderate to high elevations in prostate cancer risk. Additionally, genetic polymorphisms which affect androgen metabolism have been identified and linked to prostate cancer risk.