- Eliciting Autoimmunity to Ovarian Tumors in Mice by Genetic Disruption of T Cell Tolerance Mechanisms
- Role of Prohibitin in Ovarian Cancer Growth and Apoptotic Mechanisms
- Improving Quality of Life for Women Confronting Ovarian Cancer
- Development and Characterization of Animal Models
Eliciting Autoimmunity to Ovarian Tumors in Mice by Genetic Disruption of T Cell Tolerance Mechanisms
Posted December 10, 2008
Brad, Nelson, Ph.D., British Columbia Cancer Agency, Victoria, British Columbia, Canada
Dr. Brad Nelson from the British Columbia Cancer Agency received a Fiscal Year 2000 (FY00) New Investigator Award to study how ovarian tumors evade the immune system leading to metastatic disease in patients with intact immune systems. Dr. Nelson developed a novel mouse model that allows analysis of CD4+ and CD8+ T cell responses to ovarian tumors over time and after various immune interventions. Tumors within this mouse model express a modified version of the neu oncogene, commonly expressed in ovarian tumors. Dr. Nelson found that CD8+ T cells specific for the modified neu antigen were highly responsive to ovarian tumors, causing regression of advanced disease in 75 percent of cases, without the need for surgery or chemotherapy. Dr. Nelson also found that deletion of a negative regulator, Cbl-b, from CD8+ T cells resulted in increased T cell proliferation and tumor regression, thus revealing a potential target for improving T cell therapy against ovarian cancer. More recently, Dr. Nelson received an FY08 Idea Award for his proposal entitled "Control of Disease Recurrence by Tumor-Infiltrating T Cells in Ovarian Cancer." This research will be the first to explore the hypothesis that chemotherapy induces mutations in the tumor genome that result in new tumor antigens which in turn trigger T cell responses. There is good evidence that such T cell responses may delay or prevent tumor recurrence in many patients. The identification of these T cell stimulating antigens could lead to the development of improved immunotherapy for ovarian cancer.
Yang T, Wall EM, Milne K, Theiss P, Watson P, and Nelson BH. 2007. CD8+ T cells induce complete regression of advanced ovarian cancers by an interleukin (IL)-2/IL-15-dependent mechanism. Clinical Cancer Research 13:7172-7180.
Dr. Winston Thompson is studying and characterizing the antiproliferative and tumor-suppressive properties of prohibitin and its possible contribution to the development of chemoresistant ovarian cancer. Prohibitin is an evolutionarily conserved gene that is ubiquitously expressed, negatively regulates cell proliferation, and links to sporadic breast cancer as a result of mutations. However, while it is known that the gene is not mutated in epithelial ovarian cancer, little else is understood about the mechanism of action for prohibitin gene products in ovarian tumor ontogeny.
With funding from a Fiscal Year 2002 Department of Defense Idea Development Award, Dr. Thompson discovered the first comprehensive evidence for the expression of prohibitin and its relevance to ovarian cancer development. Dr. Thompson showed that prohibitin is markedly overexpressed in epithelial cells of serous and endometrioid adenocarcinoma of the ovary, and this overexpression is associated with inhibition of both cell growth and the onset of programmed cell death, or apoptosis, in ovarian cancer cells.
Based on recent findings indicating that the repressor of estrogen receptor activity (REA) is a prohibitin splice variant, Dr. Thompson conducted experiments to determine the role of these molecules in growth suppression and induction of apoptosis by estrogen antagonists (the current endocrine therapy of choice in ovarian cancer). The study showed that 1) prohibitin and REA are expressed in ovarian cancer cells and physically interact with each other in both the mitochondria and nucleus, 2) small interfering RNA-mediated knockdown of prohibitin expression in the estrogen receptor-positive and -negative ovarian cancer cell lines treated with estrogen antagonist resulted in cytotoxic-induced apoptosis, and 3) overexpression of prohibitin protected these cells from cytotoxic-induced cell death. These findings provide the first experimental evidence that a strategy to reduce prohibitin content in ovarian cancer cells may be useful in combination with conventional chemotherapy in therapeutic treatment of ovarian cancers that developed chemoresistance.
Thompson WE, Asselin E, Branch A, et al. 2004. Regulation of prohibitin expression during follicular development and atresia in the mammalian ovary. Biology of Reproduction 71(1):282-290.
Gregory-Bass RC, Olatinwo M, Xu W, et al. 2008. Prohibitin silencing reverses stabilization of mitochondrial integrity and chemoresistance in ovarian cancer cells by increasing their sensitivity to apoptosis. International Journal of Cancer 122(9):1923-1930.
Mary Daly, M.D., Ph.D., Fox Chase Cancer Center, Philadelphia, Pennsylvania; Nancy Avis, Ph.D., Wake Forest University, Winston-Salem, North Carolina; Sandra Zakowski, Ph.D., Rosalind Franklin University of Medicine and Science, North Chicago, Illinois
Dr. Mary Daly, of Fox Chase Cancer Center, is studying quality of life (QOL) issues in women undergoing prophylactic oophorectomy. Many women at high risk for ovarian cancer elect surgical removal of the ovaries as a preventive measure. With funding from an Ovarian Cancer Research Program Fiscal Year 1999 (FY99) Idea Development Award, Dr. Daly's team compared populations of women matched in age, race, education, marital status, and BRCA gene mutation status, and whether they did or did not proceed with prophylactic surgery.
Dr. Daly's team showed statistically significant short-term differences, with the surgery group experiencing increased hot flashes and night and cold sweats, and decreased physical and social functioning and frequency of sexual activity and pleasure. This was due to the abrupt drop in hormone levels following ovary removal, particularly in premenopausal women. Managing these symptoms is an important area of clinical intervention; however, despite these short-term menopause-like symptoms, women in the surgery group reported an extremely high level of satisfaction and confidence in their decision.
Dr. Nancy Avis, of Wake Forest University, received FY00 New Investigator Award (NIA) funding to study QOL among women with ovarian cancer. The primary objective was to identify those issues of greatest concern to women in the three treatment stages: newly diagnosed with ovarian cancer, in treatment, and post-treatment, with a secondary objective to assess changes in QOL across the different stages of care. Questionnaires were administered to participants after diagnosis and prior to (baseline), during, and following chemotherapy, and after any recurrence. Overall, QOL and physical problems were most pronounced at baseline and improved over time during treatment. Social support and absence of comorbidities were significantly associated with better QOL. The emotional well-being of patients improved faster for those with higher educational attainment, although similar emotional well-being scores were reported after two years for all women regardless of level of education. Lastly, interventions to improve QOL among women with ovarian cancer would be most effective when made available immediately following diagnosis.
Dr. Sandra Zakowski, of the Rosalind Franklin University of Medicine and Science, is another recipient of the FY00 NIA and is attempting to improve QOL for ovarian cancer patients and their partners through emotional expression in journal writings. Subjects in the intervention group were asked to write about their deepest thoughts and feelings related to their cancer experience for 20 minutes each day for 3 consecutive days. In contrast, the control group was asked to write about trivial, non-emotional assigned topics. Follow-up assessments were performed at 1 week, 3, 6, and 9 months post-intervention.
Dr. Zakowski's research team has promising preliminary results suggesting that patients, especially those with a low score for the trait of neuroticism and/or a high score in extraversion, benefitted from this intervention. Overall, this study has provided valuable information about the relations between emotional expression, personality, and psychological adjustment in cancer patients. These findings have significant implications for clinical interventions as well as future research in the field of psycho oncology.
Publication for Dr. Daly:
Daly M. 2006. Ovarian cancer risk - reducing surgery: A decision-making resource. Available to the public at no cost.
Publication for Dr. Molly Brewer:
Fang CY, Daly MB, Miller SM, et al. 2006. Coping with ovarian cancer risk: The moderating effects of perceived control on coping and adjustment.British Journal of Health Psychology 11(Pt 4):561-580.
Publication for Dr. Avis:
Finch A, Beiner M, Lubinski J, et al. 2006. Hereditary ovarian cancer clinical study group. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 mutation.Journal of the American Medical Association 296(2):185-192.
Publications for Dr. Zakowski
Quartana PJ, Laubmeier KK, and Zakowski SG. 2006. Psychological adjustment following diagnosis and treatment of cancer: An examination of the moderating role of positive and negative emotional expressivity. Journal of Behavioral Medicine 29:487-498.
Zakowski SG, Ramati A, Morton C, et al. 2004. Written emotional disclosure buffers the effects of negative social interactions on distress in cancer patients. Health Psychology: Official Journal of the Division of Health Psychology, American Psychological Association 23:555-563.
Abstracts for Dr. Daly:
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Ovarian cancer is the second most common malignancy of the female genital tract in the United States, but the lack of effective screening tools results in over 70% of cases being diagnosed during the final, metastatic stage of the disease. Progress in the fight against ovarian cancer has been hampered by a number of factors, including the lack of a valid animal model that would permit the development of improved diagnostic tools and the assessment of chemopreventive agents and potentially curative therapeutics. The Congressionally Directed Medical Research Programs Ovarian Cancer Research Program has played a pivotal role in sponsoring the development of novel animal models of ovarian cancer.
Drs. David Gershenson and Molly Brewer, from the University of Texas M. D. Anderson Cancer Center, chose to study the rhesus macaques in their chemoprevention studies. They treated the monkeys with oral contraceptives and a synthetic vitamin A or retinoid and examined biomarkers in ovarian biopsies for model assessment. The team found that these nonhuman primates serve as an excellent model for ovarian cancer chemoprevention due to drug tolerance, ease of surgical intervention, close genetic relationship to humans, and availability.
Dr. Gustavo Rodriguez, from the Evanston Northwestern Healthcare Research Institute, characterized the domestic laying chicken as an animal model for ovarian cancer prevention research. Readily available, these hens spontaneously develop ovarian cancer at a high rate. Since they ovulate frequently (almost daily), it is possible that the pathogenesis of these cancers may mimic the pathogenesis of ovarian cancer in women, which is characterized by increasing risk associated with an increased number of lifetime ovulatory events. Furthermore, studies have demonstrated that the clinical and molecular features of ovarian cancer in chickens and women are similar in a number of important areas, including molecular pathways, biomarkers, and pattern of metastatic dissemination. Thus, Dr. Rodriguez believes that the chicken model has considerable value for comparative studies of ovarian cancer progression and should be more widely considered and used.
Drs. Rong Wu and Kathleen R. Cho, from the University of Michigan, established a novel mouse model of endometrioid carcinoma induced by conditional inactivation of tumor suppressor genes (Apc and Pten) in the mouse ovarian surface epithelium. The tumors were grossly apparent within 6 weeks of the induction, and they resembled human tumors morphologically and genetically. The research team continues to develop this model as a tool for preclinical testing of novel therapeutics targeting Apc and Pten signal transduction pathways.
Another mouse model for both endometriosis and ovarian cancer has been successfully developed by Dr. Tyler E. Jacks of the Massachusetts Institute of Technology. The hallmark of the new model is the use of oncogenic K-ras in combination with inactivated Pten. The model will serve as invaluable tool for the in vivo testing of molecularly targeted chemotherapy as well as conventional anti-cancer agents.
Publications for Dr. David Gershenson and Dr. Molly Brewer:
Brewer M, Utzinger U, Satterfield W, et al. 2001. Biomarker modulation in a nonhuman rhesus primate model for ovarian cancer chemoprevention. Cancer Epidemiology, Biomarkers and Prevention 10:889-893.
Publications for Dr. Molly Brewer:
Brewer M, Baze W, Hill L, et al. 2001. Rhesus macaque model for ovarian cancer chemoprevention. Comparative Medicine 51(5):424-429.
Brewer M, Ranger-Moore J, Satterfield W, et al. 2007. Combination of 4-HPR and oral contraceptive in monkey model of chemoprevention of ovarian cancer. Frontiers in Bioscience 12:2260-2268.
Publication for Dr. Rong Wu and Dr. Kathleen Cho:
Wu R, Hendrix-Lucas N, Kuick R, et al. 2007. Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/ß-catenin and PI3K/Pten signaling pathways. Cancer Cell 11(4):321-333.
Publication for Dr. Tyler Jacks:
Daikoku T, Tranguch S, Trofimova IN, et al. 2006. Cyclooxygenase-1 is overexpressed in multiple genetically engineered mouse models of epithelial ovarian cancer. Cancer Research 66(5):2527-2531.
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