Resham Bhattacharya, PhD
Therapeutic targeting of Bmi-1 in ovarian cancer
While platinum-based drugs continue to be the foundation of therapy for ovarian cancer, chemoresistance remains the main challenge for effective management of recurrent disease. The development of new therapeutic strategies to combat ovarian cancer is needed. This study will examine the therapeutic potential of Bmi-1, a polycomb group (PcG) gene, in ovarian cancer and chemoresistance. Bmi-1 plays a key role in regulating the ability of normal stem and progenitor cells to grow. This group showed that ovarian cancer cell lines and tumor tissue have a higher Bmi-1 expression than normal ovary cells. They also found that a micro-RNA that regulates Bmi-1 when present in sufficient quantities is less abundant in ovarian cancer. Finally, they showed that reducing Bmi-1 in cancer cells made the cell less able to grow and susceptible to chemotherapy. Bmi-1 potentially plays a key role in mediating drug resistance in ovarian cancer. As such, Dr. Bhattacharya and her team will evaluate the clinical significance of Bmi-1 in ovarian cancer by comparing gene expression to stage/grade and outcome and determine the benefit of targeting Bmi-1 in disease progression in a mouse model.
Xuefang Cao, MD, PhD
Roswell Park Cancer Institute
Granzyme B-Dependent Regulatory T Cell Function in Ovarian Cancer
While effector lymphocytes are known to mediate anti-tumor immune responses, regulatory T cells (Tregs) have recently been found to promote tumor progression in ovarian cancer patients. Perforin and granzyme B are cytotoxic molecules previously known to be utilized by effector lymphocytes to kill tumor cells. However, Dr. Cao's recent studies suggest that Tregs utilize the perforin/granzyme B pathway to suppress anti-tumor immune responses. Therefore, Dr. Cao and his team will study ovarian cancer patients and mouse models to characterize the contribution of this pathway in effector lymphocyte-mediated anti-tumor immunity vs. Treg-facilitated tumor progression, and to dissect the mechanisms of granzyme B-dependent Treg function.
Daniela Dinulescu, PhD
Brigham and Women's Hospital
Nanotechology-based Therapy Targeting Platinum Resistant Disease
An exciting new hypothesis in ovarian cancer biology is that tumor development is driven by cancer stem cells, which are resistant to standard chemotherapies and consequently responsible for the high rate of tumor relapse seen in patients. Animal models, which accurately recapitulate the human disease, used in Dr. Dinulescu's laboratory constitute great tools for defining the key roles that ovarian cancer stem cells play in tumor initiation and resistance to chemotherapy. Furthermore, they provide her team with unique, relevant systems in which to screen novel nanotechnology-based therapies specifically targeting ovarian cancer stem cells that show increased efficacy and lower toxicity than currently available chemotherapy drugs.
William Foulkes, PhD
McGill University Health Center
Novel target discovery in hereditary ovarian cancer by deep sequencing
Ovarian cancer is an important cause of death and inherited susceptibility accounts for a substantial fraction of this cancer. Moreover, advances in knowledge of hereditary forms of cancer have led to insights into the more common, non-hereditary forms. Technological innovation is a key to the generation of knowledge and has recently brought revolutionary changes in the ability to study cancer. Here, Dr. Foulkes and his team will harness the power of "deep sequencing" to discover mutations that are important in ovarian cancer. This pilot study could lead to important discoveries that will help us in our struggle to better understand this often fatal disease.
Xiaolong He, PhD
University of Illinois
The role of microRNA miR-124 in ovarian cancer
Based on his previous work and recent results, Dr. Xiaolong He hypothesizes that microRNA miR-124 may function as a tumor suppressor. In this study, two specific aims are proposed to strengthen the hypothesis. Aim 1 is to examine the levels of miR-124 in human ovarian tumors and thus establish the clinical relevance of this hypothesis. Aim 2 will explore why miR-124 is reduced in ovarian cancer cell lines. Should Dr. He's hypothesis ultimately prove correct and supported by experimental results, it will have a significant impact on our understanding of how ovarian cancer develops and likely lead to new approaches to treat this fatal disease.
Stephen Howell, MD
University of California, San Diego
Identification of drugs that increase cisplatin uptake by inhibiting CTR2
CTR2 has shown to be a particularly attractive target against which to develop a drug that both inhibits tumor growth and sensitizes to platinum drugs. In this project, Dr. Howell will establish a robust assay to evaluate the function of CTR2 that can be used to identify molecules that can serve as the starting point for subsequent structure-activity studies and refinement of structure to produce a lead compound for pre-clinical testing. Dr. Howell's group feels that this can be achieved by first screening to find molecules that enhance cisplatin toxicity, then conducting a secondary screen that directly measure the cellular uptake of cisplatin and its interaction with DNA. The specific aims are to 1) establish a primary assay that detects a CTR2-specific increase in the toxicity of a low concentration of cisplatin and 2) establish a series of secondary screens that quantify the CTR2-dependent cellular accumulation of cisplatin and its ability to damage DNA.
Sandra Orsulic, PhD
Cedars-Sinai Medical Center
Determinants of Drug Sensitivity in BRCA Deficient Cells: The Role of TUBB4 in Resistance to Paclitaxel
Currently, post-operative chemotherapy for patients with sporadic and BRCA-associated ovarian cancers includes treatment with taxanes and platinum. However, there is an indication that patients with BRCA-associated cancers respond less favorably to taxanes. Dr. Orsulic has identified that a target of taxanes, TUBB4, is upregulated in BRCA1-deficient cells. She and her team will test the hypothesis that TUBB4 plays a role in modulating cell chemosensitivity to paclitaxel. The results of this project will impact the use of taxanes as standard of care for patients with advanced ovarian cancer and allow for the better identification of patients who are less likely to benefit from this drug.
Andre Lieber, MD, PhD
Fred Hutchinson Cancer Research Center
Clonality Analysis in Ovarian Cancer
In preliminary studies, Dr. Lieber's laboratory has identified new markers for ovarian cancer ovca stem cells. In this new study, his team will continue to address the concept of ovarian cancer stem cells and the phenotypic plasticity of ovarian cancer cells. Dr. Lieber proposes that various subsets of ovca stem cells exist that may alter phenotype depending on external factors (such as chemotherapy). He will be using a new approach to determine whether tumors arise from a single progenitor cell by tracking lentiviral intergration sites in primary ovarian tumors grown in mice with and without cisplatin treatment. This study will expand his team's search for cancer stem cell markers and their attempt to track single cancer stem cells in tumors after transplantation into mice, and will contribute to a better understanding of treatment resistance of ovarian cancer.
Andrew Wilson, PhD
Vanderbilt University Medical Center
The Role of the Nuclear Orphan Receptor TR3/Nur77 in Ovarian Cancer
Preliminary results have led to the hypothesis that TR3 is a marker of chemotherapy-induced apoptosis and a potential therapeutic target in ovarian cancer. In this study, three aims will be investigated by Dr. Wilson and his team. First, knockdown studies will be done to determine if TR3 is mechanistically involved in the tumor cell response to HDAC inhibitors or DNA-damaging agents. In the second aim, mitochondrial translocation will be assessed using immunoflourescence and subcellular fractionation. Lastly, TR3 expression will be correlated with response to therapy in both cultured cell lines and in human ovarian cancer specimens. Results will provide a valuable extension of Dr. Wilson's work to determine the utility of TR3 as a biomarker and therapeutic target for future treatment of ovarian cancer.