By David N. Leff
This has been a good week for the future treatment of prostate cancer.
It was nothing like last week's feeding frenzy over angiogenesis, which tripled Entremed's stock price for a while. There weren't even any striking in vivo results in a mouse model of prostate carcinoma (PC).
But whatever future clinical progress is reported in PC therapy may well derive from two in vitro advances in decrypting the secret code of prostate tumor progression.
Today's Proceedings of the National Academy of Sciences (PNAS), dated May 12, 1998, offers one key to that code; this week's issue of Nature, dated May 7, 1998, offers another. Both focus on the secret, subversive role of testosterone, the male androgen hormone, in driving PC tumors to grow and spread. (See BioWorld Today, Oct. 15, 1996, p. 1.)
The PNAS article bears the title: "From estrogen to androgen receptor: A new pathway for sex hormones in prostate." Its lead author is postdoctoral molecular biologist Shuyuan Yeh, in the laboratory of research oncologist Chawnshang Chang, at the University of Rochester, in New York.
"Most physicians treat prostate cancer by trying to block its androgen pathway," Yeh told BioWorld Today. "They don't want the androgen to continue to activate the androgen receptor, which eventually makes the tumor more severe. And when they do so, they never know when the cancer will come back again."
Once a PC tumor has broken out of the prostate gland's capsule wall and begun to metastasize other organs, the preferred treatment is palliative. Surgical or chemical castration cuts off the production of testosterone, which drives the tumor's growth. A synthetic form of the female hormone estrogen, diethylstilbesterol (DES), also targets the androgen receptor, which acts as a transcription growth factor.
During embryogenesis, this system governs development of the male genital apparatus. Later in life, a gene mutation, environmental insult or other unknown factors may turn up the receptor to fuel the prostate cancer.
"We tried to dissect what other mechanism can activate the androgen receptor," Yeh recounted. "If we can modulate this factor, it may be another curative way to think about other drugs that can block this interaction, or lower its sensitivity to other activation factors. Our data in PNAS show that wild-type estrogen may not be the good curative agent."
Chang and his co-authors found that estrogen activated the androgen receptor in human prostate cancer cells, in the presence of a specific co-activator that they discovered.
Artificial Estrogen Beats Nature's Own Hormone
This molecule enhances the gene-regulating action of the hormone complexed to the receptor, the team found. What's more, that artificial DES has better tumor-palliating effects than natural estrogen, because the cofactor works with the wild-type hormone but not with pharmaceutical DES. The latter has more potent anti-androgen action, with fewer side effects.
Partial androgen sensitivity is a hallmark of Reifenstein's syndrome, which occasions ambiguous male genitalia and reproductive disability.
In one Reifenstein's patient they examined, Yeh recalled, "from the androgen level he seemed OK. He had normal estrogen and testosterone synthesis. So then we determined that he had some defect in the androgen receptor. He had a gene mutation that truncates the receptor protein, so it never functions. Actually, some pharmaceutical companies are trying to use our testing system to select new and better anti-androgen drugs to block this pathway."
Without naming names, she said that among such interested firms that have contacted Chang's lab, one is American; another, German. "They are doing some testing in their own companies," she said.
"The next step we wish to do," Yeh concluded, "is to test such drugs in the mouse with our system, and bring it from the cellular to the animal level. Also, we want to knock out the gene-regulating cofactor we found."
Urologic cancer surgeon Edward Messing chairs the urology department at Rochester. "Virtually every patient who succumbs to PC — 40,000 men each year — dies of a disease that initially was stimulated by androgens," Messing told BioWorld Today. Then, when patients either were castrated or had androgen withdrawal therapy, they had a response. But now their tumors are growing despite the continuance of androgen withdrawal therapy.
"This PNAS paper," he concluded, "is the first demonstration that an estrogen can turn on the androgen receptor, and also turn on genes that normally only respond to androgen stimulation."
IL-6 — Alleged Tumor-Promoting Perpetrator
In the current issue of Nature, the PC paper's title is: "Requirement for Erb2 for signaling by interleukin-6 in prostate carcinoma cells." Its lead author is postdoctoral molecular biologist Yun Qiu, in the laboratory of retrovirologist Hsing-Jien Lung, at Case Western University, in Cleveland.
Interleukin-6 (IL-6) is an immune system cytokine of all trades. It promotes the production of antibodies. It's a growth factor for hybrid cells. It induces fever. And much more.
"Most people probably don't work on IL-6 in the prostate cancer cell lines," Qiu told BioWorld Today. "But in the mid-1990s, scientists at the National Cancer Institute demonstrated that most of the prostate cancer cell lines express the IL-6 receptor. But nobody knew why. It's a very bizarre but interesting observation. So that's the reason we pursued it."
The co-authors' pursuit led them to a kinase of the epidermal growth factor (EGF) receptor family. One family member is Erb2, which, Qiu observed, "has been implicated in tumorigenesis, along with the EGF receptor. Amplification of EGF," she went on, "has been found in a brain tumor, and Erb2 amplification has been observed associated with breast and ovarian tumors. So we were very excited about these findings.
"Right now we report finding that the IL-6 cytokine can activate Erb2 in the prostate cancer line. That's our hypothesis; it hasn't been proved yet. Nobody has ever demonstrated Erb2 is involved in cytokine signaling."
Qiu said the findings should have clinical potential.
"For example," she concluded, "we want to continue to study what other signaling pathway in prostate cancer can be activated by IL-6. Hopefully, we can find some candidate target which can serve for new drug development." *