Activated Stat5 protein in prostate cancer can predict outcome

August 20, 2005 -- Researchers from Lombardi Comprehensive Cancer Center at Georgetown University found that testing for an activated Stat5 protein in prostate tumor tissue effectively predicts which men have a form of prostate cancer that may become more aggressive and life threatening.

Stat5 (short for Signal Transducer and Activator of Transcription 5) is a protein which, when activated, signals cancer cells to continually grow and survive. It is a critical survival protein for human prostate cancer cells.

Marja Nevalainen

Marja Nevalainen, M.D., Ph.D., assistant professor in the Department of Oncology at Lombardi and principal investigator of this new study, previously discovered that Stat5 is activated by prolactin and that prolactin was locally expressed in the epithelial tissue of 54% of 80 human prostate cancer specimens with positive correlation with high Gleason scores and activation of Stat5. She identified prolactin and tyrosine kinase Jak2 as components of a signaling cascade that activates Stat5 in human prostate cancer cells. This means, she wrote, "they are potential molecular targets for pharmacological intervention."

Until drugs capable of blocking this cascade are developed, tested and available, the first step is to use Stat5 to identify high risk prostate cancer. Nevalainen and colleagues have now found that the Stat5 protein in the nucleus of prostate cancer cells was a significant predictor of which patients would develop a worrisome recurrence years after their prostate cancer was initially treated.

The study investigated prostate cancer biopsies or prostate cancer tissues obtained from surgery from 357 prostate cancer patients, and matched active Stat5 levels with outcome.

Given further validation, the findings offer hope that a biomarker can be developed to help oncologists and urologists to identify patients that are more likely to have a recurring and/or eventually life-threatening prostate cancer. Specifically, these patients with potentially aggressive prostate cancer should be actively treated and closely monitored in contrast to men with less aggressive prostate cancer who may safely choose watchful waiting, especially if they are elderly, the researchers say.

Sorting out the few aggressive prostate tumors from the many that are indolent is a problem that has plagued the treatment of prostate cancer, said Marja Nevalainen, M.D., Ph.D., assistant professor in the Department of Oncology at Lombardi Comprehensive Cancer Center and principal investigator of the study.

"Most patients diagnosed with prostate cancer have slow-growing tumors that don't need aggressive therapy, but doctors do not have a way to identify the few men whose cancer is potentially dangerous. The result is that many patients are over-treated," she said.

"If future studies with Stat5 continue to show that it can help in predicting disease outcome, then we can test tumor biopsy samples for Stat5 and tailor treatment accordingly," Nevalainen said.

In the study, Georgetown researchers found that patients with "mid-grade" tumors who had high levels of activated Stat5 in their prostate cancer cells were 1.7 times more likely to experience disease progression compared to patients without activated Stat5. That corresponds to a 15-year, progression-free survival of 46 percent versus 62 percent, respectively.

"Mid-grade tumors are the most difficult to predict for the clinical outcome," said Nevalainen, "therefore, the most immediate use of Stat5 in prostate cancer as a marker would be for identification of the subgroup of mid-grade prostate cancers that are likely to progress early to androgen-independence and metastatic disease," said Nevalainen. "We feel that patients in this group who test positive for activated Stat5 should not remain treated with watchful waiting only, but should be actively and extensively treated."

When biopsy samples from all the patients in the study were analyzed and Stat5 readings were compared to their outcome, those with activated Stat5 had a progression-free survival rate of 44 percent, compared to 65 percent in patients whose cancer was free of activated Stat5.

These findings are the latest in a series of studies led by Nevalainen highlighting the role of Stat5 in prostate cancer development.

Among Nevalainen's earlier findings:

• Stat5 protein is particularly plentiful in the most aggressive prostate cancers, which have often spread by the time they are diagnosed.
• Stat5 can be experimentally inhibited - active Stat5 protein can be stopped before it reaches the DNA of the cell and triggers growth. This research has led to work to develop a pharmacological agent for human use. "There are only few treatment options available for advanced prostate cancer now, and we hope that we can develop a drug that might offer hope for patients with aggressive prostate cancer in the future," she said.

Prolactin (PRL) exerts growth-promoting activities in breast cancer as well as in prostate cancer and possibly prostate hyperplasia (BPH). In a review of prolactin agonists, in April 2005 a team at the French National Institutes of Health (Paris) claimed that "The most recently developed antagonist, delta-1–9-G129R-hPRL, is "the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist." The discuss "to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL receptor antagonists in patients."