A drug in testing to treat atherosclerosis significantly inhibited the growth of ovarian cancer in both human cell lines and mouse models, according to a study by researchers at UCLA's Jonsson Comprehensive Cancer Center. The finding is the first report of a peptide — in this case, apoA-I mimetic peptides — being used to fight malignancies.
The study follows a previous discovery by the same group showing that a protein in patients called apolipoprotein A-I (apoA-I) may be used as a biomarker to diagnose early-stage ovarian cancer, when the disease is typically asymptomatic and much easier to treat. These earlier findings could be vital to improving early detection, as more than 85 percent of ovarian cancer cases present in advanced stages, when the disease has already spread and patients are more likely to have a recurrence after treatment, said Dr. Robin Farias-Eisner, UCLA chief of gynecologic oncology and co-senior author of the study with Dr. Srinu Reddy, a UCLA professor of medicine.
"The vast majority of ovarian cancer patients are diagnosed with advanced disease, and the vast majority of those, after surgery and chemotherapy, will eventually become resistant to standard therapy," Farias-Eisner said. "That's the reason these patients die. Now, with this peptide as a potential therapy, and if successful in clinical trials, we may have a novel effective therapy for recurrent, chemotherapy-resistant ovarian cancer, without compromising the quality of life during treatment."
The study was published Nov. 1 in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.
In their previous work, Farias-Eisner, Reddy and their research teams identified three novel biomarkers that they used to diagnose early-stage ovarian cancer. In September 2009, the U.S. Food and Drug Administration cleared the first laboratory test that can indicate the likelihood of ovarian cancer, the OVA1 Test, which includes the three biomarkers identified and validated by Farias-Eisner, Reddy and their teams.
They observed that one of the markers, apoA-I, was decreased in patients with early-stage disease and speculated that the protein might be protective and could be preventing disease progression.
The protein apoA-I is the major component of HDL, or "good" cholesterol, and plays an important role in reverse cholesterol transport by extracting cholesterol and lipids from cells and transferring it to the liver for extraction. The protein also has anti-inflammatory and antioxidant properties. Because lipid transport, inflammation and oxidative stress are associated with the development and progression of cancer, Farias-Eisner and Reddy hypothesized that the reduced levels of apoA-I in ovarian cancer patients may be causal in disease progression.
Mice that were engineered to have many copies of the human apoA-I gene showed very little cancer development when induced with ovarian cancer, while mice without the extra copies of apoA-I showed much more disease. The mice with extra copies of the apoA-I gene also lived 30 to 50 percent longer than those that didn't receive it.
Farias-Eisner and Reddy wanted to treat the mice that had more cancer with the protein apoA-I, but it was too large to conveniently administer, having 243 amino acids. The researchers then turned to apoA-I mimetic peptides — only 18 amino acids in length — which are being tested for cardiovascular diseases. That project had been ongoing for a number of years at UCLA, said Reddy, who is also a part of the cardiovascular research team led by Dr. Alan M. Fogelman, executive chair of the UCLA Department of Medicine.
"The smaller peptides mimic the larger apoA-I protein and provided us with agents we could give to the mouse to see if it was effective in fighting ovarian cancer," said Reddy. "One of the peptides was being tested as an experimental therapy for atherosclerosis, so we already have some information on how it's being tolerated in humans, which would be vital information to have if we progressed to human studies in ovarian cancer."
The peptide, thus far, has caused little to no side effects in atherosclerosis patients, Reddy said, a hopeful sign that it might be well tolerated in ovarian cancer patients.
The mice that were given the peptide by injection had about 60 percent less cancer than the mice that did not receive the peptide, Farias-Eisner said. The peptide also was given in drinking water or in mouse food and proved to be as effective when administered in that way.
"It was an exciting result," Farias-Eisner said. "It looked like we had something that could be ingested or injected that might be very effective against ovarian cancer progression."
Farias-Eisner said the peptide avidly binds oxidized lipids, one of which is known to stimulate cancer cells to survive and multiply. In the mouse studies, the mice that received peptide had significantly lower levels of this cancer-promoting lipid.
An early-phase clinical trial is being planned to test the peptide in patients with aggressive ovarian cancers that are resistant to chemotherapy, a group of patients whose median survival is just 40 months. Farias-Eisner hopes the study will be started and completed within two years.
The study was funded by the Women's Endowment, the Carl and Roberta Deutsch Family Foundation, the Joan English Fund for Women's Cancer Research, the National Institutes of Health and the West Los Angeles Veterans Affairs Medical Center.
UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson Center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2010, the center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 of the last 11 years.