Roswell Park Comprehensive Cancer Center researchers have found that the effect of a key gene driving an aggressive, recurrent and often incurable form of prostate cancer is dose-dependent, opening new avenues for therapies that overcome resistance to treatment of advanced disease.
They are presenting the results of this research at the American Association for Cancer Research (AACR) Annual Meeting 2018, which continues through April 18 in Chicago, Ill.
Prostate cancer is one of the most common cancers affecting American men.
About 8% of those affected will develop advanced cancer.
While newer targeted treatments designed to interfere with molecules known to encourage the growth and spread of cancer cells are effective for some patients, a majority of patients with this advanced and aggressive form of prostate cancer will succumb to their disease.
The Roswell Park team previously developed an experimental model of treatment-resistant prostate cancer and identified a new therapeutic target called Ezh2 — an enzyme that has a widespread effect on the expression of genes that drive resistance to prostate cancer therapy.
Prostate cancer becomes more aggressive as EzH2 levels rise, and drugs that inhibit this enzyme are currently in clinical development.
When the research team used these drugs in their model, formerly treatment-resistant prostate cancer tumours became treatable once again.
For the current research, the researchers developed a new model in which they deleted this enzyme’s gene in prostate cancer, Ezh2, expecting that this would render tumours less aggressive and easier to treat.
Surprisingly, deleting the gene and removing the cancer-driving enzyme had the opposite effect: prostate cancer tumours became even more aggressive and harder to treat. This research is the first to show that the effect is dose-dependent.
“It is unclear why decreasing Ezh2 levels by partly removing its gene makes prostate cancer easier to treat while removing it entirely makes the disease more — not less — aggressive,” says Dr. Kristine Wadosky, who will outline the team’s findings in a podium presentation at the meeting. “This unexpected result provides us with completely new implications for use of drugs against this target in prostate cancer patients. We are now looking at mechanisms of resistance, hoping to better understand this effect and identify those patients who will benefit most from a new class of targeted drugs.”