1 August 1997 Urot97\Endothel.MS-- 1,000 words
Endothelin linked to PCa bone metastases;
can a drug block its effects?
Baltimore, MD--Another molecular step in prostate cancer bone metastases has been identified, and a drug to block its effects is starting clinical trials.
Endothelin-1 (ET-1) is a normal component of semen which is consistently elevated in prostate cancer, and which seems to play an important role in the tumor-stromal interaction, said Joel B. Nelson, MD, assistant professor of urology and oncology at Johns Hopkins School of Medicine, Baltimore, MD.
ET-1 has two receptors in the prostate. One of those receptors, ETA, seems to control the effect of ET-1--and can be blocked. [NOTE: ET subscript A]
"We hope blocking the ETA receptor will alleviate pain, will inhibit the osteoblastic response of bone to prostate cancer, and potentially tumor growth."
Another receptor, ETB, is consistently lost in prostate cancer. "We now have a molecular explanation for that loss," said Dr. Nelson. The ETB receptor gene is methylated, which shuts it off, he recently discovered. And this shutoff is "potentially reversible," he said. [NOTE: ET subscript B]
ET-1 stimulates osteoblasts and inhibits osteoclasts, explained Dr. Nelson. Tumors that express ET-1 also increase bone formation in mice, he reported at the AUA's 92nd annual meeting in New Orleans.
ET-1 is a potent vasoconstrictor which is found in even higher concentrations (500-fold) in ejaculate than in plasma, although its function has not been established.
Dr. Nelson found that the plasma immunoreactive levels of ET-1 were significantly elevated in the blood plasma of men with metastatic prostate cancer, and every human prostate cancer cell line that he tested also produced ET-1. He found ET-1 in situ in 14 of 14 primary cancers, and in 14 of 16 metastatic sites.
ET-1 induces prostate cancer proliferation directly, and enhances the mitogenic effects of insulin-like growth factor I, insulin-like growth factor II, platelet-derived growth factor, basic fibroblast growth factor, and epidermal growth factor in vitro.
ET-1 has 2 receptors on the prostate--ETA and ETB. During the progression to metastases, ETA expression remains steady, while ETB expression is reduced so low that Dr. Nelson could not find any functional receptors in any prostate cancer cell line. Instead, a critical section of the ETB gene was methylated.
Several compounds are available to block (or to stimulate) the functioning of the receptors, by plugging the site that binds to ET-1. A compound that blocks the ETA receptor inhibited the growth-stimulating effect of ET-1, in vitro. A compound that blocks the ETB receptor, and another compound that stimulates the ETB receptor, had no effect on ET-1 stimulated-growth, Dr. Nelson found.
So now the Johns Hopkins group is starting a Phase I clinical trial of a drug which blocks the ETA receptor.
That drug is ABT 627, a new ETA receptor antagonist, developed by Abbott Laboratories, which can be taken orally.
Michael A. Carducci, MD, Assistant professor of oncology and urology, at Johns Hopkins is principal investigator of the Phase I human trials, and is currently recruiting patients with advanced hormone-refractory prostate cancer. The work is funded by CAP Cure, the National Institutes of Health, and Abbott.
"Gene methylation is a naturally occurring process where genes that don't need to be expressed are shut off," said Dr. Nelson. The classic example is the X chromosome inactivation in women. The ETB methylation, though, is an acquired somatic alteration in the gene, not a germ line event.
Other genes have been identified that undergo methylation in prostate cancer, and one, GST-pi, is methylated in almost every prostate cancer, said Dr. Nelson. There are compounds that reverse methylation, but they are too toxic for therapy. [NOTE: Greek letter pi]
"The ETB receptor is responsible for the clearance of endothelin-1," said Dr. Nelson. So the receptor may be sopping up excess ET-1. "Loss of this receptor would lead to a higher concentration of endothelin-1, locally and in the circulation," he said. And that would promote bone metastases.
"The ETB receptor is also linked to unique pathways inside the cell," said Dr. Nelson. "So when the ETB receptor is lost, the unique functions associated with it are also lost. It may be a classic tumor suppressor."
Overall, about 70% of the prostate cancer lines had the ETB gene methylation. Dr. Nelson found methylation in human prostate cancer cell lines, in primary prostate cancers, and in prostate cancer metastases. In contrast, normal tissues contained only the unmethylated gene.
That incidence of 70% is far more common than most other genetic changes, said Dr. Nelson. (In contrast, only about 3% of prostate cancers have the human prostate cancer 1, or HPC-1, mutation.)
"It's a pretty good clue that you're on to something important," said Dr. Nelson. "If prostate cancer goes down the path where this particular gene is methylated, and it's a common event, one has to ask, what does this gene control and why is it so important?"
The other 30% of prostate cancers could have the same mutation by a different mechanism. In addition to methylation, a gene could be disrupted by mutation or allelic loss, "and this particular gene sits on a part of the genome where allelic loss is extremely common," said Dr. Nelson. (The ETB receptor gene is located on the long arm of chromosome 13, or 13q, along with BRCA2, the breast cancer gene; RB1, the retinoblastoma gene; and DBM, the disrupted-in-B-cell-malignancy gene.) "So it's reasonable to speculate that some of the people who don't have methylation may have allelic loss," he said.
The methylation occurs at a site on the gene where it would be expected. The gene contains a sequence that includes the region that regulates transcription. This region, which is called a 5' CpG island, contains regions on the DNA which contain repeats of the "CG" sequence. The "C," or cytidine, nucleotides are the targets for methylation. The CpG islands are clustered at the beginning of those genes that are controlled by methylation, said Dr. Nelson.
So methylation is a standard genetic switch--one of the switches that may be flipped in prostate carcinogenesis.