The aromatase enzyme occurs naturally in the body, but for women with breast cancer, it can cause trouble.
It’s the final chemical gatekeeper in the body’s process of creating estrogen, a hormone that's important for normal growth and function. Unfortunately, estrogen also boosts most breast cancers, which need it to grow.
Shiuan Chen, Ph.D., director of the Division of Tumor Cell Biology.
Since hampering aromatase can choke off estrogen production, blocking the enzyme has become an important part of treatment among most postmenopausal women with breast cancer, according to
|Shiuan Chen is studying an emerging epigenetic drug for breast cancer treatment. (Photo by Markie Ramirez)|
Several drugs — letrozole, anastrozole and exemestane among them — inhibit aromatase. And studies have shown that these drugs offer postmenopausal breast cancer patients higher chances of survival.
But there are drawbacks.
“Unfortunately, these drugs affect the production of estrogen throughout the whole body, and that means women experience the effects of estrogen depletion, like joint pain and bone loss,” Chen said. Also, patients can become resistant to these drugs.
Looking for new strategies, Chen and his colleagues trained their sights on the gene that produces human aromatase.
Scientists now know that the human aromatase gene goes into overdrive in breast cancer cells that need estrogen to grow. That means cancer cells create large amounts of aromatase, which they then use to make their own estrogen, fueling their own growth.
So the researchers turned to a drug called panobinostat. It’s a new type of drug, called an epigenetic therapy, that may suppress the aromatase gene in breast cancer cells more than in normal cells. That means the cancer cells would not be able to produce their own estrogen, but normal cells would.
Chen’s team found that panobinostat stifles two specific regions of the aromatase gene that are critical to making the aromatase enzyme, stunting aromatase production in breast cancer cells.
Their findings could pave the way for a breast cancer treatment strategy that reduces side effects associated with today’s aromatase inhibitors.
“We are especially enthusiastic about the results, because they also indicate that when panobinostat is paired with letrozole — an aromatase inhibitor already in use today — it effectively suppresses proliferation of hormone-responsive breast cancer cells,” Chen said. “We believe lower doses of letrozole potentially could be used in this sort of therapy strategy, which would mean much less toxicity to patients.”
And combining the drug with letrozole goes even further: The researchers found that using the two drugs together made each of them significantly more effective at fighting breast cancer cell growth in the lab than either drug alone.
The work has led to a phase I clinical trial pairing panobinostat with letrozole for breast cancer. City of Hope’s Thehang Luu, M.D., assistant professor in the Department of Medical Oncology & Therapeutics Research, is pursuing a phase II clinical trial that would include City of Hope patients.
“Aromatase inhibitors have made a significant difference for our patients with hormone-dependent breast cancers, but we want to make that strategy even more effective, with fewer side effects,” Luu said. “We hope that a new generation of drugs can do that.”