The prostate-specific antigen (PSA) test took a beating this fall, with several long-term studies revealing it is not a stellar prognostic indicator. However, new findings on the genetic and molecular workings of prostate cancer are giving researchers new hope for better diagnostics and treatments for prostate cancer.
The original champion of the PSA test, Stanford University urologist Thomas A. Stamey, M.D., lost faith in PSA as a marker for prostate cancer after analyzing data from 1,300 radical prostatectomies performed over the last 20 years. He says that, today, PSA reflects only prostate enlargement. "There is an urgent need for serum markers that reflect the size and grade of this ubiquitous cancer," Stamey and colleagues wrote in October 2004 in the Journal of Urology.
A relatively low PSA level is also not a guarantee that cancer does not exist. In the Prostate Cancer Prevention Trial, 15% of men with PSA levels less than 4.0 ng/mL had prostate cancer, and 15% of those had high-grade disease.
PSA was dealt another blow in Octoberthis time over its inability to predict survival in men who had undergone radiation therapy for their cancer. The study, by researchers at Fox Chase Cancer Center, revealed that "PSA bounce"a rise and then decline in PSA level following radiation treatmentshould not be a reason to prescribe hormonal therapy. Without additional treatment, men with PSA bounce lived as long as those who didn't experience the bounce.
Without good markers to distinguish aggressive cancer from slow-growing disease, decisions on whether and how to treat are difficult. Treatment side effects, such as urinary incontinence and sexual dysfunction, are long-term and common.
Enter a new wave of candidate targetsHedgehog, the tumor suppressor gene PTEN, the androgen receptor, and the HER2 proteinthat may prove themselves as markers for disease. Each may also play a role in shifting prostate cancer diagnosis and treatment to the more targeted approaches that have proved successful against cancers such as chronic myelogenous leukemia (CML).
Measuring Hedgehog
Hedgehog, a cell signaling molecule that drives normal development and regeneration in the prostate and several other tissues, is greatly activated in prostate cancers that are likely to spread, says Philip A. Beachy, Ph.D., a Howard Hughes Medical Institute (HHMI) investigator at Johns Hopkins University School of Medicine in Baltimore.
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The hope is that Hedgehog may be used to distinguish lethal cancers from those requiring minimal therapy; however, there is no blood test for high Hedgehog activity in the prostate. "We have to find something secreted by cells that have high Hedgehog pathway activity, and it would have to be prostate specific," Beachy explained, since Hedgehog is active in epidermal tissues, such as the lining of the stomach, that frequently regenerate. His group is trying to develop such a test.
Hedgehog is a treatment target as well. Beachy and colleagues found that cyclopamine, a drug derived from the corn lily, a plant that grows in mountain meadows in the western United States and that causes birth defects in sheep, blocks the Hedgehog pathway. In mouse studies, cyclopamine caused permanent regression of grafted human and rodent tumors. This research was published online in Nature on September 12.
Even at 6 to 8 months after treatment ended, tumors did not regrow. "There is good evidence in a number of tissues that cancers are propagated by a minority of cells that seem to have properties of stem cells," he explained. "These cancer stem cells probably derive from tissue stem cells." Their results suggest that the cancer stem cells were wiped out, Beachy said. Hedgehog and another signaling pathway called Wnt have roles in stimulating self-renewal for stem cells.
There probably is some type of subpopulation of stem cells that is important for prostate cancer metastasis, said Kenneth J. Pienta, M.D., principle investigator of the Prostate SPORE at University of Michigan, "but if you try to look globally at the tumor and metastatic lesions, you can't see it for all the noise." He was senior author on a paper published December 15 in Cancer Research in which researchers used rapid autopsy in men who died of hormone-refractory prostate cancer. They found tremendous heterogeneity at the phenotype and genotype level in metastatic prostate cancer cells, even within the same patient.
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Meanwhile, several drug companies are developing Hedgehog antagonists, and Beachy is pushing hard to get cyclopamine into clinical trials, including working with farmers in Utah to harvest large quantities of corn lily.
Tumor Suppressor Loss
A tumor suppressor gene called PTEN is also the object of drug development efforts. At least one quarter of men with prostate cancer have tumors that are missing PTEN, and these tend to be more aggressive tumors.
HHMI investigator Charles L. Sawyers, M.D., and his colleagues at the University of California at Los Angeles Jonsson Cancer Center showed several years ago that tumors with a PTEN mutation are very sensitive to inhibitors of an enzyme called mTOR. "When you've lost PTEN, mTOR activity gets turned up and tumors become dependent on it for their growth."
Now the researchers have identified a set of biomarkers that show whose prostate tumors will respond to an experimental mTOR inhibitor called CCI-779 (Wyeth). "We can use these tests first to select the patients most likely to respond and then simultaneously to monitor the effect of the treatment," said UCLA researcher George V. Thomas, M.D., lead author of the study, which was published in the December 15 issue of Clinical Cancer Research. Patients diagnosed with high-risk disease are being recruited at UCLA, the University of Texas M. D. Anderson Cancer Center in Houston, and Fox Chase Cancer Center in Philadelphia for a clinical trial to see if the drug is hitting the target and stopping cancer growth.
Tumor Escape Mechanisms
Hedgehog and PTEN lesions are genetic changes that likely cause primary initiation or expansion of the prostate cancer, according to Sawyers. Two other targets that Sawyers has been working on are androgen receptor overexpression and HER2 binding, two related changes in the tumor that give it an advantage under the selective pressure of hormone ablation therapy. "It's the way a tumor is able to escape therapy. The tumor very clearly needs the androgen receptor," Sawyers said.
Prostate tumor cells often become resistant to hormone ablation therapy, gaining the ability to proliferate even in the absence of androgen, their normal growth signal. Antiandrogen therapy stops working and the tumor becomes lethal. In a series of studies published online in Nature Medicine on December 21, 2003, Sawyers and colleagues used DNA microarrays to look for gene changes in drug-resistant prostate cancer cells. The one consistent change they found was an overexpression of the gene for the androgen receptor.
An abundance of receptors makes the tumor resistant to hormone ablation. The extra receptors still need to be bound by androgen, however. The researchers found that the receptors overcome the androgen shortage by converting antiandrogen drugs into agonists.
When they realized that the androgen receptor still needs a ligand to function, Sawyers and colleagues became very interested in understanding how to regulate the receptor. "It's such a druggable target, it provides a compelling rationale to keep hammering away at it with new approaches."
One approach is to screen for drugs that resist the conversion from antagonist to agonist. The crystal structure of the receptor bound to androgen has been solved. "A larger magnitude of progress could be had if we understood the crystal structure of the androgen receptor bound to antagonist," Sawyers explained. That missing roadmap has slowed down development of more effective androgen antagonists. "The estrogen receptor field is much further along because they've seen those structures and have used that information to guide drug design."
The androgen receptor relies on members of the ERBB family of kinases for its stability, but in a different way than previously thought. Although earlier work has strongly implicated the epidermal growth factor receptor (EGFR) as a key modulator of the androgen receptor, Sawyers' group found that signals from HER2, not EGFR, were required for androgen receptor function. HER2, via interaction with its sister molecule HER3, is the key, Sawyers found. These results may explain why gefitinib (Iressa, Astra-Zeneca), an EGFR inhibitor, has shown limited success in clinical trials for prostate cancer.
More promising drugs include the HER2 inhibitor omnitarg (Genentech), which is in phase II studies for prostate cancer, as well as some newer small molecule inhibitors that appear to be more active than gefitinib against HER2. Researchers are looking for ways to measure the quantity in a patient's tumor of the HER2/HER3 heterodimer. They could use the heterodimer as a marker to choose patients to receive anti-HER2 therapy and to measure patient response. "The heterodimer is the most relevant," Sawyers said.
"Like all cancers, we're going to come at this with combinations," he added. "I'd like an optimized drug that hits the ligand binding pocket of the androgen receptor, plus the HER2 story tells us we can also imagine a kinase inhibitor that would indirectly stop the tumor by working as an antiandrogen." Going after Hedgehog and/or PTEN could be part of the mix as well, he said.
Pienta agreed. "There will clearly be a combination of attacking the cancer at the androgen receptor level, the cell signaling level, the classic chemotherapy level, and the tumor stroma level," targeting elements that support metastasis to bone, for example. Drugs are being developed in all these areas, he said.
"We were totally in the dark a few years ago," Sawyers added. "Now we're really beginning to have a molecular framework to think about how to apply these drugs."
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