Ongoing scientific and clinical research programs keep Mayo Clinic Cancer Center at the forefront of discovery and ensure that patients have access to the newest and most effective medical treatments and diagnostic methods. Mayo provides an ideal environment for clinical research, and the Women's Cancer Program is one of the leading programs in the Center, pursuing cutting-edge research into new diagnostic or therapeutic options, prevention efforts and ways to improve quality of life. Through better understanding of the nature of cancer, researchers in gynecologic surgery, medical and radiation oncology, medical genetics, pathology and many other specialties work together to give individuals with women's cancers the widest possible range of treatment options.
Mayo scientists conduct laboratory-based research, studying cancer cells and the biological mechanisms within those cells to better understand the origin and growth of cancer. Other researchers engage in population science or epidemiology research, examining large groups of individuals to find patterns of risk for specific cancers.
Clinical trials, or clinical research studies, test the most promising discoveries to determine the benefits for patients and compare new treatments to today's standard of care. Many are the result of translational research, which involves researchers and clinicians determining how laboratory results may be applied to benefit patients diagnostically and therapeutically.
At Mayo Clinic Cancer Center we participate in these types of research, and apply this information to find answers for each unique individual.
Finding better ways to treat cancer is a top priority, but also important is finding ways to help people cope with their cancer diagnosis and treatment. We conduct psychosocial and quality of life research studies to look at the emotional, psychological, social and spiritual effects of cancer and cancer treatment. This research seeks to find ways to help individuals and their families adjust to the demands of treatment and life post-diagnosis.
The following summarize some of our ongoing research initiatives:
Substantial evidence suggests that inflammation, apoptosis (cell death), and immune responses are linked to the development of ovarian cancer. NF-κB is the name of a family of proteins that regulates the expression of numerous genes that are central to these processes. It is possible that genetic variations in NF-κB may modify the activity of the NF-κB proteins and lead to differences in how each individual person experiences inflammation, apoptosis, and immune responses. These differences might increase or decrease a woman's risk of developing ovarian cancer, so it is essential to identify which genetic variations are important.
Dr. Goode's research team recently received funding from the National Institutes of Health to examine whether these genetic variations are associated with the risk of developing ovarian cancer. This research will analyze DNA taken from blood samples of participants recruited in ongoing ovarian cancer studies at Mayo Clinic and at Duke University in Durham, N.C. The main goal of the study is to identify the subset of genes related to the NF-κB family which are most relevant to ovarian cancer. These results will be used for the identification of future strategies to prevent and treat ovarian cancer.
Ovarian cancer, unlike many other cancers, often does not present with obvious early symptoms; there may be no bleeding, pain or visible change in the body to signify a problem. Therefore, at the time of diagnosis, ovarian cancer is typically advanced. A screening test for ovarian cancer would be of great benefit to patients as treatment for early stage disease is much more likely to be effective. The Women's Cancer Program is capitalizing on Mayo's expertise and collaborative research ties in proteomics, biostatistics and bioinformatics to develop possible screening techniques. Researchers hope to develop a screening test for ovarian cancer, much like the PSA test for prostate cancer.
Mayo Clinic received a National Institutes of Health research grant to develop and refine the technologies for complex proteomics analysis. The project is ongoing, now as a collaborative effort with North Carolina State University.
Mayo researchers are collaborating with David Muddiman, Ph.D., formerly of Mayo Clinic and now at the Department of Chemistry at North Carolina State University—one of a dozen research centers worldwide capable of the advanced, comprehensive, systematic study of proteins necessary to move this research forward. The Mass Spectrometry Group will compare blood and tissue cells from women with ovarian cancer and without ovarian cancer. The group will look at patterns in thousands of expressed proteins. The identification of these patterns and their association with health or disease may lead to the discovery of proteins that are responsible for causing ovarian cancer, and could be used as disease markers in a screening test.
There are other cancer centers with the ability to do proteomic research, but the collaborative efforts encompassing Mayo Clinic's archive of ovarian tissue samples and the proteomics analyses expertise of Dr. Muddiman's group is a powerful combination. The ovarian tissue bank was created at Mayo Clinic in 1991 and is one of the most comprehensive such archives in the world. As part of this screening project, the Women's Cancer Program collects preoperative blood samples from women with ovarian cancer. Each tissue or blood sample is correlated with the medical records for the patient from whom the sample was taken. Today, the ovarian tissue bank includes more than 1,500 samples, and it continues to grow.
Almost 80 percent of women with ovarian cancer respond positively to chemotherapy at the beginning of treatment, but over time, the majority of ovarian cancers develop resistance to chemotherapy. We do not fully understand why or how this change happens. Researchers in the Women's Cancer Program hypothesize that therapies directed to a particular cell-signaling pathway can overcome chemotherapy resistance in ovarian cancer. They are studying a new agent, 17-AAG, which targets this cell-signaling pathway.
The investigators have taken 17-AAG through rigorous testing in the lab and in animal models with promising results. Early clinical trials (Phase I) with 17-AAG in combination with chemotherapy have also shown promising results in ovarian and primary peritoneal cancers. The next phase of study (Phase II) will explore the use of 17-AAG in combination with the chemotherapy drug gemcitabine (Gemzar®) in patients with ovarian and primary peritoneal cancers.
Many laboratory studies are being conducted to try to identify what makes cancer cells behave differently than normal cells. Dr. Shridhar and her fellow investigators use molecular biology techniques to determine which genes are expressed differently in cancer cells. The researchers then use cell biology methods to determine how the changes in gene expression affect how the cancer cells grow or respond to chemotherapy agents. This is a powerful approach to identifying targets for the development of new drugs.
Dr. Shridhar's team has found that HSulf-1, an enzyme that removes sulfate residues from proteins, is expressed at much lower levels in ovarian and breast tumors than in normal ovarian and breast epithelial cells. When cancer cell lines were forced to increase their HSulf-1 expression back to normal levels, they grew more slowly and were much more sensitive to the chemotherapy drugs cisplatin and taxol.
Current studies are defining how HSulf-1 is lost in tumors and how expression of HSulf-1 helps the chemotherapy agents kill the cancer cells. It is hoped that these studies will lead to ways to restore the ability of cisplatin and taxol to kill cancer cells that have become resistant these drugs.
Viruses have considerable promise as therapeutic agents for cancer because of their ability to get inside cells and then destroy them. Scientists at Mayo Clinic have been researching the effect of measles viruses on cancer. Measles viruses use a particular receptor on the surface of cells to get into the cell. This receptor is found in higher-than-expected concentrations on ovarian cancer cells, making ovarian cancer a good target. Ovarian cancer is also a particularly appealing target as the virus can be administered in large quantities in the peritoneal cavity, where ovarian cancer cells are often found in large numbers.
Mayo Clinic researchers, working with animal models, have found that a particular strain of measles virus developed from a human vaccine strain is able to kill ovarian cancer cells without damaging noncancerous cells. This strain of measles virus can be genetically altered so that it produces a telltale signature that can be tracked. This signature, or biomarker, allows researchers to monitor the presence of the virus, in a noninvasive manner, by analyzing the patient's blood. The biomarker greatly enhances our understanding of what happens when the virus is introduced into the body.
The Phase I clinical trial evaluating intraperitoneal administration of this measles virus (MV-CEA) started in July 2004. Currently, 17 patients have received increasing doses of MV-CEA virus with no adverse events. We plan Phase II trials to continue evaluation of this promising novel therapeutic approach.
Resistance to chemotherapy and recurrence are great hurdles that need to be overcome to make strides in ovarian cancer. The insulin-like growth factor (IGF) system may be a key to both of these. The IGF system, which is tightly regulated in normal tissues, is a complex pathway of circulating growth stimulatory factors called ligands. These ligands, namely IGF-I and IGF-II activate growth when they interact with a receptor found on the surface of cells called the IGF-1 Receptor (IGF-1R). In many cancers, including ovarian, this system is uncontrolled, leading to cancer growth. In addition to this, the system provides signals to cancer cells that help them avoid death in response to chemotherapy.
Researcher in the Women's Cancer Program have hypothesized that the IGF system signaling may be a key factor in ovarian cancer recurrence, by allowing small amounts of unseen cancer to remain when a patient is otherwise thought to be in remission. In addition to this, there is evidence that the IGF system is a major reason why the recurrent cancers are not very responsive to standard chemotherapy. Current investigations are taking place with an inhibitor of the IGF-1R, which is the major 'cog' in the IGF 'machine'. Initial experiments in ovarian cancer are encouraging. Inhibition of the IGF pathway has demonstrated anticancer activity in all ovarian cancer cell lines in the laboratory and greatly enhances the activity of other agents, including inhibitors of another growth factor pathway- the HER system. Mayo investigators are testing whether IGF-1R inhibition (+/- HER receptor inhibition) can improve the ability of chemotherapy to keep ovarian cancer away in an animal model. The best sequence of agents in the animal model will be the basis of a clinical trial proposal.
The standard treatment for patients with advanced ovarian cancer following initial surgery is intravenous paclitaxel and carboplatin. About 80 percent of patients respond to these chemotherapy drugs. Unfortunately 50 percent to 75 percent of patients have a recurrence of disease within one to two years of treatment, secondary to drug resistance, and eventually die as a result of disease progression. There is a clear need for additional treatment options that address the problem of chemotherapy drug resistance in ovarian cancer. There are data suggesting that angiogenesis, the growth of new blood vessels to the tumor, plays a significant role in chemotherapy drug resistance. Giving an anti-angiogenic drug (a drug which prevents the growth of new bloods vessels to a tumor) along with paclitaxel and carboplatin may decrease drug resistance and improve the activity of these chemotherapy drugs.
Sunitinib (Sutent®) is an anti-angiogenic drug. It has demonstrated antitumor activity in drug resistant cells. Sunitinib has great potential to enhance the activity of standard chemotherapy drugs such as paclitaxel and carboplatin. This study will look at the antitumor /angiogenesis effects on ovarian cancer cells when sunitinib is given alone or in combination with paclitaxel and carboplatin. Dr. Copland’s laboratory has developed human ovarian cancer cell lines from patients who were drug resistant to paclitaxel and carboplatin, and other cell lines from patients who are sensitive to these drugs. The researchers hope to identify genes that may correlate with a demonstrated response to sunitinib and reversal of the drug resistance. It is expected that the identification of specifically altered genes in resistant ovarian cancers in these preclinical experiments will allow the design of clinical trials that will demonstrate an improved response to treatment of ovarian cancers.
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