Institution: Beckman Research Institute of the City of Hope
Investigator(s): Melanie Ruth Palomares , M.D., M.S. -
Award Cycle: 2005 (Cycle 11)
Initial Award Abstract (2005)
Introduction: A class of drugs called aromatase inhibitors (AIs) are effective in breast cancer (BC) treatment, and may also be effective for BC prevention in women who have entered menopause. Herbal dietary supplements are a popular form of cancer prevention for healthy women. Our group demonstrated that grape seed extract (GSE) acts like an AI in mice. This led us to conduct a human clinical trial to test the AI activity of GSE. The prospective collection and storage of blood during the course of the trial will allow us to study markers of BC risk reduction and potential long-term side effects. The purpose of this proposal is to utilize resources from the ongoing trial to gather data to gain further understanding of the spectrum of GSE action, as well as its potential long-term adverse effects.
Hypotheses: We want to address five main questions: (1) Does GSE adversely affect the testosterone-related hormones? These hormones are present in low levels in women and are important for maintaining bone health, libido, memory, and a general sense of well-being. High levels are associated with elevated breast cancer risk and unwanted hair growth. (2) Does GSE adversely affect cholesterol or blood clotting proteins that are associated with heart disease? (3) Does GSE reduce insulin resistance? This has been associated with breast cancer risk. (4) Does GSE reduce new blood vessel growth? This also has been associated with breast cancer development. Finally, (5) can previously unknown anti-cancer effects of GSE be discovered through the use of a new technology called proteomics?
Methodology: Twenty-four postmenopausal women at increased risk for BC are being studied in our ongoing GSE trial. Blood is being collected and stored during the course of the study. This proposal outlines aims to use the stored blood to measure how GSE affects the following laboratory studies: testosterone-related hormones, cholesterol and blood clotting factors, insulin studies, a specific blood vessel growth factor, and blood protein profiles via proteomics.
Innovative elements: The ongoing clinical study represents the first step in applying the AI effect of GSE discovered at the laboratory bench, by our group with CBCRP support, to women with high risk for developing BC. The additional laboratory studies proposed will provide crucial information in determining the usefulness of GSE as a natural BC prevention agent, as well as provide a better understanding of how GSE works in humans. No one knows the effects of AIs or GSE on the factors proposed. Further, both sensitive and precise laboratory methods and cutting-edge exploratory protein profiling technology will be used in these experiments.
Advocacy involvement and human issues: With BC being the most common cancer in American women, development of a well-tolerated, inexpensive, natural product that reduces breast cancer risk would have an enormous public health impact. If GSE can be shown to be effective in reducing the risk of BC, while at the same time preserving overall health, it could become an economical and noninvasive alternative for breast cancer risk reduction. The fact that GSE is inexpensive and widely available will allow greater access to underserved women with a high risk for BC.
Final Report (2008)
A class of drugs called aromatase inhibitors (AIs) are effective in breast cancer (BC) treatment, and may also be effective for BC prevention in women who have entered menopause. Herbal dietary supplements are a popular form of cancer prevention for healthy women. Our group demonstrated that grape seed extract (GSE) acts like an AI in mice. This led us to conduct a human clinical trial to test the AI activity of GSE.
We initially encountered some difficulty in recruiting healthy women in the community under the original eligibility criteria that led to some delay in subject accrual. Specifically, many women interested in participation did not meet the requirement of elevated risk of breast cancer for the study. Because the aim of this Phase I trial is proof of aromatase inhibition in humans and determination of the optimal dose and duration of GSE to achieve that effect, we amended the protocol to eliminate the prerequisite of elevated Gail and Claus risk estimates for breast cancer. We also expanded the age range from 50-65 to 40-75 so that more postmenopausal women may participate.
As of February 28, 2008, the study met its accrual goals. We prescreened a total of 194 subjects and invited 35 potentially eligible subjects for a screening visit. Of those, 28 subjects were confirmed eligible and consented to participation. We enrolled 27 of those subjects, but 2 were nonadherent to the placebo run-in and therefore dropped from the study prior to GSE administration. Of the 25 subjects who were started on GSE, 22 have completed the study per protocol thus far: six subjects on dose level #1 (50 mg/day), six on dose level #2 (300 mg/day), six subjects on dose level #3 (1,000 mg/day), and four subjects on dose level #4 (2,000 mg/day). Two subjects are currently receiving 2,000 mg/day of GSE, and are anticipated to complete the study by July 2008.
At this time, results are available on the 50 and 300 mg/day doses only. We observed an overall trend suggesting estrogen suppression by the 12th week of GSE treatment at the 300 mg/day dose level. Unfortunately, pharmacokinetic analyses have been hindered due to technical difficulties with measuring four different procyanidin dimers with optimal sensitivity. However, these analyses are currently underway, and we expect results shortly.
As far GSE effects on the proposed secondary endpoints, no significant measurable changes in androgen levels, or in VEGF and other angiogenesis-related proteins, were observed at the 50 and 300 mg/day dose levels GSE. With regards to insulin metabolism, although a non-significant trend toward increased C-peptide was observed at the 50 mg/day dose level, C-peptide was overall unchanged at the 300 mg/day dose level. There were no observable effects of GSE on either IGF1 or IGFBP3 at either the 50 or 300 mg/day dose levels.
We anticipate completion of accrual and treatment of all subjects on this trial by July 2008. Completion of data collection and analysis will follow immediately after trial completion.
Symposium Abstract (2007)
Suppression of estrogen through inhibition the enzyme aromatase is thought to have potential for breast cancer risk reduction. While pharmaceutical agents have an established role in breast cancer treatment, foods and dietary compounds are now also being explored for cancer prevention. The purpose of this research is to screen foods for aromatase inhibitory activity, identify the chemicals responsible for that activity, perform preclinical studies evaluating the ability of a food extract to inhibit aromatase-mediated cancer development, and translate promising natural aromatase inhibitors into clinical trials.
Our laboratory tested seven fruit juices and found that juice from red grapes was the most effective in inhibiting aromatase activity. We subsequently found that extracts of red grape juice and wine suppressed aromatase in a dose-dependent manner. We demonstrated that the extracts also suppressed proliferation of an aromatase over-expressing, estrogen receptor-positive breast cancer cell line, MCF-7aro. Furthermore, oral administration of the extract completely halted aromatase-induced hyperplasia in a mouse model of aromatase-mediated breast cancer. We then showed that procyanidin B dimers, the major phytochemicals in the seeds and skins of grapes, are the chemicals responsible for the anti-aromatase activity. Lastly, we performed feeding experiments with grape seed extract and demonstrated inhibition of aromatase-mediated mammary tumor growth in mice.
Based on this preclinical data, we hypothesize that post-menopausal women could reduce their breast cancer risk with a grape seed extract dietary supplement through suppression of estrogen. A Phase I chemoprevention trial to evaluate the anti-aromatase activity of grape seed in post-menopausal women is underway to test this hypothesis. The design of this clinical trial will be presented.
source : Grape Seed as a Natural Breast Cancer Chemopreventive Agent