An emerging epigenetic drug can directly inhibit breast cancer cells’ aromatase expression, paving the way for a breast cancer treatment strategy that could reduce the side effects associated with today’s aromatase inhibitors.
Called panobinostat, or LBH589, the drug suppresses two critical sections of the human aromatase gene in breast cancer cells, dramatically inhibiting the production of the enzyme, said Shiuan Chen, Ph.D., director of the Division of Tumor Cell Biology and principal investigator. Proceedings of the National Academy of Sciences published the findings June 15.
|Shiuan Chen is studying an emerging epigenetic drug for breast cancer treatment. (Photo by Markie Ramirez)|
“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.”
Blocking aromatase has become an important part of treatment among most postmenopausal women with breast cancer, Chen explained.
Aromatase occurs naturally in the body and serves as the final chemical gatekeeper in the body’s process of creating estrogen, a hormone that most breast cancers need to grow. Inhibiting aromatase activity can choke off estrogen production. Drugs like letrozole, anastrozole and exemestane inhibit aromatase, and studies have shown that these drugs offer postmenopausal breast cancer patients significantly improved 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,” he said. Also, patients can become resistant to these drugs.
Looking for new strategies, he and his colleagues trained their sights on the human aromatase gene.
Scientists now know that in hormone-dependent breast cancer cells, the human aromatase gene actually throws aromatase expression into overdrive. That means cancer cells themselves express aromatase, which they then use to create their own estrogen. Chen believes that panobinostat represents a new type of drug that will preferentially suppress the expression of aromatase and estrogen formation in breast cancer cells.
Chen’s lab, which was one of the first three to clone human aromatase complementary DNA, previously found that two regions on the human aromatase gene in breast cancer cells are critical to producing aromatase. Now they have found that panobinostat stifles these two regions, stunting the expression of aromatase from breast cancer cells.
|Thehang Luu (Photo by p.cunningham)|
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 proliferation in the lab than either drug alone.
The work has led to collaboration with panobinostat’s developer, Novartis, and the University of Pittsburgh, which opened 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.”
Study co-authors include Jingjing Ye, of the Center for Biomedicine & Genetics, and Ikuko Kijima, Ph.D., formerly of Chen’s lab, as well as Dean Evans, Ph.D., of the Novartis Institutes for Biomedical Research. The preclinical research project is supported by grants from Susan G. Komen for the Cure and the National Cancer Institute.