Karen Abbott, PhD
University of Georgia
Targeting Tumor-Specific Glycosylation: Discovery of Novel Membrane Receptors
Dr. Abbott's work is focused on discovering new tumor-specific targets on the surface of cancer cells. Tumor-targeted therapy regimens will have less toxic side effects to normal tissues, and lead to a better quality of life for patients. This project is based on a recent discovery of a unique type of carbohydrate (glycan) found on proteins that cover the surface of ovarian tumor cells and not normal ovarian cells. The membrane receptors that help this glycan stick to the surface of tumor cells will be identified and subsequently used for the development of tumor-targeted therapeutics in the future.
Karen Cowden Dahl, PhD
The Role of ARID3B isoforms in Ovarian Cancer and Chemoresistance
Around 70% of women diagnosed with ovarian cancer have advanced disease and the prognosis is very poor. Treatment for ovarian cancer consists of surgery followed by chemotherapy. One of the contributing factors to the poor prognosis for advanced ovarian cancer is due to tumor cells becoming resistant to chemotherapy. This project aims to understand how a new overexpressed gene (ARID3B) is regulated in ovarian cancer and how different forms of this gene contribute to chemoresistance. These studies will further the understanding of genes that are involved in ovarian cancer and chemoresistance in order to better treat ovarian cancer patients.
Daniela Dinulescu, PhD
Brigham and Women's Hospital
Experimental Models to Validate a Tubal Cell of Origin for Serous Ovarian Cancer
Too little is known about the genetic lesions responsible for ovarian cancer tumor initiation, and uncertainty remains over the specific cell or cells of origin. Data emerging from The Cancer Genome Atlas (TCGA) on the many genomic alterations in serous ovarian carcinoma has delivered a treasure trove of new candidates for investigation, but discerning which gene alterations are critical early events in cancer pathogenesis, how tumors evolve to their highly aggressive state, and which pathways represent the best therapeutic targets will require a large scale collaborative research effort. Animal models developed in Dr. Dinulescu's lab, which accurately recapitulate the human disease, constitute great tools for defining the key roles that ovarian cancer cells in the ovarian surface epithelium and distal fallopian tube play in tumor initiation and resistance to chemotherapy. Furthermore, they provide us with unique, relevant in vivo systems in which to screen novel molecularly targeted therapies as they become available.
Thuy-Vy Do, PhD
University of Kansas Medical Center
Preclinical Evaluation of Aurora A Kinase and PARP Inhibitor Combination Therapy
Women carrying mutations in the breast-cancer associated 1 or 2 (BRCA1/2) genes are at higher risk for developing epithelial ovarian cancer. BRCA1/2 play critical roles in repairing DNA and helping genes avoid mutation. Interestingly, BRCA1/2 is not functioning optimally in cases of sporadic epithelial ovarian cancer, and BRCA2 and Aurora A interact in cells to regulate genomic stability. Dr. Do will test the hypothesis that Aurora A and BRCA1/2 interact to mediate DNA repair and cell growth. An Aurora A kinase inhibitor and a PARP inhibitor will be tested as therapies for ovarian cancer.
Alexander Nikitin, MD, PhD
Role of Stem Cells in Ovarian Cancer
Understanding of epithelial ovarian cancer development is critical for designing effective diagnostic and therapeutic approaches. During recent years it has become increasingly clear that cancers may arise from stem and progenitor cells. However, the location of the stem cell compartment of the ovarian surface epithelium that give rise to cancer cells remains unknown. Dr. Nikitin will explore a newly identified stem cell compartment in the ovary and determine properties of these stem cells and their contributions to epithelial ovarian cancer.
Daniel Powell, PhD
University of Pennsylvania
Preclinical Evaluation of Costimulated CIR Therapy for Ovarian Cancer
Adoptive immunotherapy is extremely effective for triggering tumor regression in patients with malignant melanoma. To develop adoptive T-cell therapy for epithelial ovarian cancer, we have created a chimeric immune receptor (CIR) that redirects the immune system against alpha-folate receptor, a protein on the surface of 90% of epithelial ovarian cancer cells. In designing this therapy, other strategies that will be taken into account including promoting growth and survival of the body's own immune cells to fight ovarian cancer. The results of Dr. Powell's work will provide preclinical data essential for clinical development.
Carrie Rinker-Schaeffer, PhD
University of Chicago
Milky Spot Macrophages: Co-Conspirators in Omental Metastasis Formation
No one knows what microenvironmental interactions control ovarian cancer metastasis. Getting this crucial information requires a fresh look from a new perspective. Recently Dr. Rinker-Schaeffer's lab made a novel connection between ovarian cancer metastatic colonization and structures on the omentum (tissues in the abdomen) that contain immune cells and are called milky spots. It is suspected that cancer cells take advantage of milky spots to promote their own survival and growth. This project will identify interactions between omental immune cells and cancer cells that can be targeted in combination with current therapies in order to suppress metastatic growth, improve quality of life, and extend disease-free survival.
Lupe Salazar, MD
University of Washington
Adoptive Transfer of Tumor Specific Th1 Cells Derived from Vaccine-Primed Patients Achieved Clinical Benefits
Adoptive immunotherapy can induce cancer regression but rarely results in cure. We have infused HER2-specific Th1 cells in breast cancer patients, and 50% of patients had a partial or complete response to the treatment. Dr. Salazar hypothesizes that Th1/Th17 immune cells that can recognize tumor cells can have enhanced therapeutic efficacy. This project will determine the optimal conditions to grow these multifunctional immune cells in the lab in order to enhance their ability to identify and target cancer cells using IGFBP2. Results from this project will lead to a phase I study of adoptive immunotherapy in ovarian cancer after priming with an IGFBP2 vaccine.
Janet Sawicki, PhD
Lankenau Institute for Medical Research
Utilizing HuR to Combat Chemotherapeutic Resistance in Ovarian Cancer
The molecular basis underlying the range of ovarian cancer patient responses to chemotherapeutic agents is poorly understood. This project will address the urgent need to stratify ovarian cancer patients for therapy and enhance currently available treatment strategies. Recently, Dr. Sawicki's lab discovered that the stress response protein, HuR, can mediate therapeutic efficacy of gemcitabine and a PARP inhibitor, two drugs currently used to treat ovarian cancer, by rapidly binding and regulating cancer-associated mRNA transcripts. Therefore, HuR may serve as both a potential predictive marker for drug efficacy and a promising target for therapeutic manipulation for the treatment of epithelial ovarian cancer.
Kavita Shah, PhD
Chemical Genetic Dissection of Aurora A Kinase in Ovarian Cancer
The function of kinases is to turn proteins on and off in cells. Aurora A kinase is one such kinase whose levels increase early in ovarian cancer and are associated with poor prognosis. By identifying the proteins that Aurora A kinase turns on and off in ovarian cancer cells that are not affected in normal cells, Dr. Shah can design drugs to inhibit Aurora A kinase from doing its job and reverse the cascade of proteins that are involved in progression of ovarian cancer. Safer drugs can be developed which target only ovarian cancer cells while avoiding normal cells.
Barbara Vanderhyden, PhD
Ottawa Hospital Research Institute
Role of PAX2 in the Etiology of Ovarian and Fallopian Tube Cancers
The origins of ovarian cancer are poorly understood but most cancers seem to arise from the surface layer of cells on the ovary or the fallopian tube. Ovarian surface epithelial cells have the ability to develop into ovarian cancer subtypes that fall into two broad categories: low-grade and high-grade. Previous work shows that changes in a protein, PAX2, occur in the earliest cancerous structures in both ovaries and fallopian tubes. Dr. Vanderhyden's lab has developed methods to isolate both ovarian and fallopian tube cells from mice and will determine how changes in PAX2 contribute to the early stages of ovarian cancer.
Christine Walsh, MD
Cedars-Sinai Medical Center
Genetic Modifiers of BRCA1-Associated Gynecologic Cancer Penetrance
Women who inherit a mutation in the BRCA1 gene have a 40% risk of developing ovarian, tubal, or peritoneal cancer. Dr. Walsh is seeking to shed light on genetic and molecular events that lead to tumor development in some women in this high-risk population but not in others. A significant difference in the genetic sequence of the PARK2 gene distinguishes BRCA1 mutation carriers that do develop cancer from those who do not develop cancer. This project will further investigate PARK2, which is mutated in other cancers and has a tumor suppressor function, by looking at its role in the biology of BRCA1-associated gynecologic cancer development.
Jian-Jun Wei, MD
MiR-182 Overexpression in Early Tumorigenesis of High Grade Serous Carcinoma
High grade papillary serous carcinoma may arise from serous tubal intraepithelial carcinoma in the fallopian tube. MiR-182 is a small RNA molecule that is significantly overexpressed in both types of carcinomas. Dr. Wei hypothesizes that miR-182 overexpression is a critical and early molecular change in papillary serous carcinoma. He will use normal fallopian tube secretory epithelial (FTSE) cell lines to investigate whether adding miR-182 in large amounts will result in tumors and whether miR-182 causes tumors via target genes BNC2 and MTSS1 known to be involved in papillary serous carcinoma. The results will provide a new marker in early detection and a potential therapeutic target for PSC.