Daniela Dinulescu, PhD
Eugene Braunwald Research Center, Harvard Medical Center
Targeted therapeutic strategies and early detection biomarkers in ovarian cancer
Epithelial ovarian cancer is the leading cause of death among gynecological cancers. We will actively discover, identify and validate disease biomarkers associated with early disease. The data collected from these key preclinical studies will be instrumental in designing successful clinical trials involving novel, molecularly targeted therapies and screening means for early detection. This work will allow us to test the efficacy of targeted therapies in ovarian cancer, improve the chemotherapies currently used, and better understand the mechanism of tumor chemoresistance. A sustained research effort in the areas of screening and treatment will dramatically improve the prognosis of ovarian cancer patients, as has been proven in other women's cancers, such as breast and cervical cancers.
Robert Jaffe, MD
University of California San Francisco
Inhibition of Telomerase to Treat Advanced Ovarian Cancer
Telomerase is an enzyme that maintains and protects the ends of chromosomes, the telomeres. While telomerase is constrained in many normal adult cells, a majority of cancers appear to depend on active telomerase for their growth, making this enzyme an attractive target for new anti-cancer therapies. Two telomerase targeting methods have been developed in the laboratory of our collaborator, Dr. Elizabeth Blackburn. Both of these approaches, hairpin siRNA and MT-TER, singly and in combination have been shown to block growth of a variety of cancer cell lines in vitro. The goal of this study is to test the efficacy of these telomerase-targeting approaches in a nude mouse model of human ovarian cancer with ascites and intraperitoneal carcinomatosis developed in our laboratory. Ultimately we hope these new methods will decrease human ovarian cancer burden and ascites and lengthen survival for women with this disease.
Elizabeth Smith, PhD
Fox Chase Cancer Center
Suppression of cyclooxygenase in prevention of menopausal gonadotropin-stimulated ovarian cancer risk
The risk of developing ovarian cancer increases rapidly in the peri- and post-menopausal periods, when ovulation ceases but the reproductive gonadotropin hormones are elevated. These gonadotropins can induce expression of certain enzymes which stimulate an inflammation-like condition that may cause changes in ovarian morphology and may promote cancer. To understand the relationship between menopause and ovarian cancer risk, these studies will investigate in the Wv mouse model, which mimics postmenopausal biology, the importance of ovulation and cyclooxygenase-1 enzyme expression on ovarian cancer development. We will also evaluate the potential to use pharmacological inhibitors of cyclooxygenases to reduce ovarian cancer risk.
Daniela Matei, MD
Atransglutaminase 2 Modulates Sensitivity to Chemotherapy in Ovarian Cancer
The most significant cause of death and illness related to ovarian cancer is its propensity to spread in the abdomen. However, the mechanisms responsible for spread are not known. We discovered that an enzyme called transglutaminase 2 (TG2) is present at high levels in ovarian tumors, in abdominal fluid recovered from patients with cancer and in ovarian cancer cells. We also found that this protein facilitates the spreading and adhesion of ovarian cancer cells to the extra-cellular matrix by modulating the function of beta integrins. We hypothesized by modulating tumor cell interaction with the microenvironment TG2 regulates the process of intra-peritoneal metastasis and the response to chemotherapy. In this proposal we will evaluate the physical and functional interaction between TG2 and integrins in ovarian cancer cells and tumors. This interaction may ultimately alter the way ovarian cancer cells respond to chemotherapy. If TG2 alters sensitivity to chemotherapy, the next step will be to test inhibitors of TG2 in conjunction with chemotherapy.
Cassian Yee, MD
Fred Hutchinson Cancer Research Center
Cellular Adoptive Immunotherapy in Treating Patients With Stage III or Stage IV Ovarian Cancer
Using NY-ESO-1, a previously discovered antigen, Dr. Cassian Yee and Dr. Naomi Hunder, both of Fred Hutchinson Cancer Research Center, are using a new technique to treat patients with late stage ovarian cancer. T cells are collected from eligible patients and responder T cells are enhanced. These are given back to the patient through IV, where the patient's immune system will recognize these cells and use them to fight the existing cancer.