- New Anti-Metastatic and Anti-Angiogenic Compound for Ovarian Cancer
- Development of a Novel Vaccine with Fusions of Dendritic and Ovarian Cancer Cells from Patients
- Regulation of Telomerase Activity in Ovarian Cancer
- Facilitating Decision-Making about Prophylactic Oophorectomy
In recent years, exciting novel therapeutic agents aimed at preventing new blood vessel formation (angiogenesis) in tumors have received considerable attention. Most notable among these agents are the compounds angiostatin and endostatin. These compounds represent a growing class of anti-angiogenic agents that are derived from extracellular matrix (ECM) and blood proteins. The ECM that surrounds cells in tissue is important for regulating many cellular functions such as growth, migration, differentiation, and survival. Transformed or malignant cells are less confined by the ECM, and consequently, tumors arise. Ovarian Cancer Research Program-supported investigators at the Burnham Institute have been working to devise compounds that restore ECM control of malignant cells. To do so, they created superfibronectin, a polymer of fibronectin prepared by mixing fibronectin and anastellin. Anastellin is a 76 amino acid peptide derived from fibronectin that was discovered and named by these researchers. Both superfibronectin and anastellin were shown to be potent inhibitors of tumor growth, angiogenesis, and metastasis in mice. They also showed that when anastellin was combined with fibrinogen, an abundant serum protein involved in blood clotting, it polymerized to form a superfibrinogen. Superfibrinogen has antitumor activity that is similar to superfibronectin and anastellin. Thus, these investigators have identified three new agents with potential therapeutic utility for treatment of ovarian cancer. The fact that these agents work following systemic rather than local administration may offer an additional advantage for treating ovarian cancer.
Yi M and Ruoslahti E. 2001. A fibronectin fragment inhibits tumor growth, angiogenesis, and metastasis. Proceedings of the National Academy of Science 98:620-624.
Investigators at the Dana-Farber Cancer Institute are pursuing a novel approach to ovarian cancer vaccine development. The research strategy involves the fusion of human dendritic cells (i.e., cells that present a substance or "antigen" to immune system cells in such a way that it is recognized as a threat) with ovarian cancer cells to generate effective antitumor immunity in patients. Preliminary work conducted by these investigators demonstrated that hybrid cells, created by the fusion of dendritic cells with cancer cells expressing the MUC1 carcinoma-associated antigen, are effective in inducing antitumor responses in mice. Mice with established MUC1-positive metastases in the lungs were cured of their disease after receiving the vaccine. Ovarian carcinoma cells from patient are killed by T lymphocytes, which are activated by fusions of dendritic cells with patients' ovarian cancer cells. Investigators plan to test the human ovarian cancer vaccine being developed in the present study in future clinical trials.
Gong J, Nikrui N, Chen D, Koido S, Wu Z, Tanaka Y, Cannistra S, Avigan D, and Kufe D. 2000. Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumor immunity. J Immunol 165(3):1705-1711.
Ovarian Cancer Research Program investigators at the University of South Florida had previously identified a genetic abnormality associated with hereditary ovarian cancer. This abnormality is found in the ovarian surface epithelium (OSE), a single layer of cells enveloping the ovary, of women at risk for ovarian cancer. The OSEs in these women demonstrate premature shortening at the ends of their chromosomes, regions referred to as telomeres, causing chromosomal instability and leading to cellular aging and death. In some cases, cells with critically shortened telomeres survive due to the reactivation of an enzyme called telomerase that maintains telomeric length and allows cells to progress toward malignant transformation. Therefore, the premise of this study is that increased telomeric instability maintained by telomerase may contribute to the malignant transformation of OSE and that telomerase represents a potentially important anti-ovarian cancer target. To test this hypothesis, an ovarian culture model system has been developed in which telomerase activity can be controlled in both normal and cancerous ovarian cells. The immediate goal of this study is to use this system to determine the molecular mechanisms that regulate telomerase activity in ovarian cancer. The long-term goals of this study are to evaluate the effectiveness of telomerase as a potential anti-ovarian cancer target and a prognostic indicator of therapeutic outcome and to design novel therapeutic modalities specifically targeted to ovarian cancer.
Thus far, this research has provided some insight into the molecular mechanisms that regulate telomerase activity in ovarian cancer; investigators have confirmed that the phosphoinositol 3-kinase (PI3-K) signal transduction pathway regulates telomerase activity in ovarian cancer. In addition, telomerase activity in OSE cells has been shown to be associated with increased cell growth, survival capabilities, and resistance to chemotherapeutically induced apoptosis or cell death. These results are of significant clinical importance because they indicate that abrogation of telomerase activity in ovarian cancer cells may increase cellular sensitivity to chemotherapeutic agents and thus may increase the efficacy of current chemotherapeutic modalities. Therefore, continued examination of the mechanisms that regulate telomerase in ovarian cancer may eventually reduce ovarian cancer mortality.
Alfonso-De Matte MY, Cheng JQ, and Kruk PA. 2001. Ultraviolet irradiation- and dimethyl sulfoxide-induced telomerase activity in ovarian epithelial cell lines. Exp. Cell Res. 267:13-27.
Alfonso-De Matte MY, Moses-Soto H, and Kruk PA. Calcium-mediated telomerase activity in ovarian epithelial cells. Arch. Biochem. Biophys. (in press).
Ovarian cancer is associated with the highest mortality rate of the gynecological cancers. Women with a family history of ovarian cancer are at especially high risk of developing the disease. Since the efficacy of available detection regimens is limited, prophylactic oophorectomy (i.e., surgical removal of healthy ovaries) has emerged as a preventive option for these individuals. Yet, few data are available on how to help women process and make decisions about undergoing prophylactic surgery. Ovarian Cancer Research Program (OCRP) investigators at the Fox Chase Cancer Center are conducting a study focusing on how women with a familial risk of ovarian cancer make decisions regarding preventive options, specifically prophylactic oophorectomy. The primary goal of the study is to explore the psychological factors that influence a woman's decision to undergo or forego the procedure. A secondary goal is to identify whether high monitors (i.e., women who typically scan for and exaggerate health threats) show a different pattern of response to the decision-making process than low monitors (i.e., women who typically distract from and minimize health threats).
Data from preliminary studies conducted by OCRP investigators reveal that cognitive (thought-associated) and affective (emotional) factors can impact decision making. Specifically, results obtained thus far indicate that perceived risk of developing ovarian cancer is positively correlated with intention to undergo prophylactic oophorectomy. Furthermore, women classified as high monitors have a higher perceived risk for developing ovarian cancer and a greater intention to undergo prophylactic oophorectomy compared to low monitors. In addition, data from 64 women who completed 3-month assessments indicate that a shift toward greater intention to undergo surgery is associated with the use of seeking emotional support as a coping strategy and younger age. However, this shift was not associated with risk status, perceived barriers to surgery, or knowledge of ovarian cancer.
Through a more systematic investigation of factors associated with decision making, OCRP investigators plan to generate a profile of decision making that will be used to develop an enhanced counseling intervention. This proposed counseling intervention will enable the prophylactic oophorectomy candidate to realistically anticipate scenarios that might develop and thereby provide a more informed basis for making a decision and dealing with the consequences. Research findings emanating from this work should allow women at high risk for developing ovarian cancer to make more informed decisions concerning their prevention and treatment options.
Miller SM, Fang CY, Manne SL, Engstrom PF, Daly MB. 1999. Decision-making about prophylactic oophorectomy among at-risk women: psychological influences and implications. Gynecologic Oncology 75(3): 406-12.
Hurley KE, Miller SM, Costalas JW, et. al. 2001. Anxiety/uncertainty reduction as a motivation for interest in prophylactic oophorectomy in women with a family history of ovarian cancer. Journal of Women's Health Gender Based Medicine 10(2): 189-199.
Fang CY, Miller SM, et al. The influence of attentional style and risk perceptions on intentions to undergo prophylactic oophorectomy among FDRs. Psychology and Health, in press.