By David N. Leff

In ¿As You Like It,¿ Shakespeare has Jacques recount the Seven Ages of Man ¿ infant, schoolboy, lover, soldier, justice, pantaloon [i.e., codger], second childishness.

About halfway through that life-spanning laundry list ¿ say, between justice and codger ¿ the prostate gland begins to hint that advancing age is soon to be reckoned with. By numerical coincidence, that men-only organ progresses through seven stages:

1. Adolescence ¿ helping to make sperm cells, and maintain male fertility;

2. Benign prostate hypertrophy (BPH) ¿ non-cancerous growth, impeding urination, usually requiring surgery;

3. Cancer in situ ¿ tumor cells causing no trouble while confined within the gland¿s capsule;

4. Invasive prostate cancer ¿ malignancy breaks through capsule;

5. Metastatic prostate cancer ¿ tumor cells infiltrate bone or lymph nodes, driven by androgen hormone (i.e., testosterone). Castration cuts off testicular source of hormone ¿ temporarily slowing androgen-dependent tumors.

6. Metastasis returns, but this time tumors are androgen-independent;

7. Death intervenes; prostate cancer kills 40,000 Americans a year. (See BioWorld Today, Nov. 17, 1999, p. 1.)

This stark, often-cited mortality statistic takes on more personal meaning when, within the present decade, celebrities who died of PC include movie stars Bill Bixby, Roddy MacDowell and Telly Savalas, France¿s chief of state, Frangois Mitterand and rock star Frank Zappa.

PC is not a Western-lifestyle disease, but worldwide. The U.S., with 15.7 deaths per 100,000 men, falls halfway down the list of 50 countries, while Japan records 3.5 per 100,000.

¿In Japan,¿ observed molecular immunologist Aya Jakobovits, vice president of research, and chief scientific officer, at UroGenesys Inc. in Santa Monica, Calif., ¿prostate cancer is not as well spread as in the U.S. But it¿s interesting that when Japanese move here, after several generations they do acquire the disease. So we believe it¿s definitely environment and diet. People are putting a lot of effort into identifying whether there is any dietary factor related to the incidence of PC. Also, are there any foods that would allow patients to survive it, or enhance their quality of life.¿

Jakobovits is one of 13 UroGenesys scientists who co-author a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Dec. 7, 1999. Its title presents a newly discovered antigenic player in PC: ¿STEAP: A prostate-specific cell-surface antigen highly expressed in human prostate tumors.¿

STEAP stands for ¿Six-Transmembrane Epithelial Antigen of the Prostate.¿ The team tracked its gene, STEAP, to the short arm of human chromosome 7, a genomic neighborhood that is no stranger to suspected cancer-causing gene sequences.¿

Disease-Mimicking Mice Made It Possible

To find their STEAP prostate-cancer antigen, the co-authors employed a stable of xenografted mice that faithfully replicate every clinical stage of prostate disease. ¿What is different between our mice and other PC animal models,¿ Jakobovits told BioWorld Today, ¿is the type of prostate gland tissues and lesions that are being propagated in the mice. Our animal model was established initially by hematologist-oncologist Charles Sawyers at the University of California, Los Angeles. That¿s one of the technologies that we licensed from UCLA at the time UroGenesys was founded, in early 1997.

¿Those mice,¿ she went on, ¿received tumors derived directly from patients who had been operated. These clinical samples were taken from different stages of the disease. So that allowed the mice to propagate tumors that reflect prostate cancer either from the primary locus, which is the prostate gland, or from bone or lymph node metastases.¿

She made the added point, ¿This also allowed us to look at the other stages of disease progression, including the transition from androgen dependence to androgen independence. And therefore that allowed us to identify and validate antigens that are clinically relevant. This unique mouse resource has enabled us to identify a large portfolio of antigens, including STEAP, which is the core of our PNAS paper.¿

Jakobovits continued, ¿As we move into the STEAP molecule, we are looking for antigens that have structural localization, which implies that they will be good therapeutic or diagnostic markers. Using this type of criteria we have generated a portfolio that currently contains over 30 antigens with implications for PC, and have all the other characteristics we are looking for. With very restricted expression in normal tissue, as well as the structure localization, they can be very good targets for therapeutic or diagnostic approaches.

¿We are looking at antigens that have usually more than one therapeutic application,¿ she went on. ¿STEAP is a good example. It¿s expressed at very high levels throughout all the stages of the disease, including androgen independence. You can target the antigen as a drug, or its antibody, to the patient, and probably eliminate all prostate cells at all stages of the disease, including normal prostate.

¿Because it¿s also expressed in androgen independence,¿ she pointed out, ¿that means that the expression of the molecule is not affected by the presence of hormones. One of the most popular current treatments for people who have recurrent disease, and advanced disease, is hormone ablation ¿ castration ¿ which eliminates the effect of the androgen.¿

Winning Ticket: Combination Therapy

¿By virtue of the fact that STEAP is not affected by the presence or absence of androgen, one can for example envision a mode of therapy,¿ Jakobovits suggested, ¿whereby if you are initiating hormone ablation therapy, you can in conjunction with it apply an antibody ¿ or a small molecule ¿ targeted to STEAP. Maybe this combination therapy would be much more powerful than the ablation by itself, for example.¿

She cited ¿current thinking that in order to have a very high level of efficacy and impact on the disease, you may need more than one approach. You may need antibody, vaccine, and small molecules in combination, with or without hormone therapy.¿ She concluded: "We are looking at all three, in discussions with a whole array of pharmaceutical and biotechnology companies, pushing very aggressively toward clinical trials sooner rather than later."