City of Hope researchers and colleagues have shown that one of the first members of a new family of drugs appears to fight metastatic breast cancer.

The drug known as vorinostat stabilized cancer growth in a small group of women who were treated for stage 4 breast cancer in a phase II clinical trial.

City of Hope researchers presented their study findings on behalf of the California Cancer Consortium at the 29th annual San Antonio Breast Cancer Symposium in December. Vorinostat belongs to a family of drugs called histone deacetylase, or HDAC, inhibitors. These agents come from advances in the field of epigenetics, a relatively new line of research that studies how genes are inappropriately turned on or off without any changes in genetic sequences themselves.

Unlike other recent anticancer strategies, which target altered genes and their gene products, epigenetic strategies seek to turn on genes that have been silenced — genes that can help put the brakes on cancer. The field of epigenetics can be traced back to early work carried out by Arthur Riggs, Ph.D., director of Beckman Research Institute, and colleagues, said George Somlo, M.D., professor and director of breast oncology in the Division of Medical Oncology & Therapeutics Research and the study’s senior author.

In the vorinostat study, participants took the drug in a pill form twice a day for two weeks, then took a week off. Overall, side effects were mild and the drug was well tolerated, said Somlo, co-director of the City of Hope Breast Cancer Program.

The drug stabilized tumor growth in four of the 14 women in the study. One woman still remains on the drug, more than 13 months after beginning treatment. “She is going on cruises and traveling around the world,” said medical oncologist Thehang Luu, M.D., the study’s principle investigator and presenter.

“We hope that this and other HDAC inhibitors can provide a novel treatment option as part of combination therapy, especially for women with triple-negative breast cancers,” Luu said, referring to cancers that do not overexpress estrogen, progesterone or human epidermal growth factor (HER2) receptors. Luu believes HDAC inhibitors and other drugs emerging from epigenetics will likely work best when combined with other drugs that battle cancer from several directions.

City of Hope researchers plan to join a phase II clinical trial for metastatic breast cancer patients that will test a combination of vorinostat, bevacizumab (an agent targeting angiogenesis) and paclitaxel, a chemotherapy drug, Somlo noted.

City of Hope researchers are investigating several HDAC inhibitors, including belinostat (PXD101), currently offered in a phase II clinical trial for patients with mesothelioma and a phase I trial for patients with advanced solid tumors. And vorinostat is in phase II clinical trials at City of Hope for two other cancers: non-Hodgkin’s lymphoma and bladder cancer. The investigations come through the California Cancer Consortium, a National Cancer Institute-funded cooperative that unites City of Hope, the University of Southern California, UC Davis and the University of Pittsburgh to conduct small studies of up-and-coming drugs. “Science is moving quickly on these therapies,” Luu said. “We’d like to be able to speed them to our patients as fast as we can.”

Breast cancer on the defensive City of Hope researchers shared recent advances at the 29th annual San Antonio Breast Cancer Symposium.

Among the many authors:

• Melanie R. Palomares, M.D., reported on the potential for genetic cancer risk assessment to educate women about their true lifetime risk of breast cancer so that they can pursue risk-appropriate cancer screening.
• Jeffrey N. Weitzel, M.D., discussed a new factor — family structure — that may be crucial in correctly estimating women’s risk of carrying a mutation in breast cancer genes BRCA 1 and 2, especially among women under age 50.
• Xin Wang, Ph.D., presented findings that the cancer-preventing drug exemestane not only inhibits aromatase, but it also destabilizes the aromatase protein with the help of proteasomes.
• Shiuan Chen, Ph.D., reported that his group has created breast cancer cell lines resistant to aromatase inhibitors and tamoxifen, an advance that may help scientists understand how cells find a way around these important breast cancer-deterring drugs, as well as provide a tool for testing new drugs to fight hormone-resistant breast cancer.