Ovarian cancer (OvCa) is the deadliest US gynecologic malignancy with a clear need for novel therapeutic approaches. Immunotherapy, a class of treatments that restores the patient’s immune system to recognize and kill cancer cells, is one promising approach to improve the outcome of OvCa patients. While current immune therapies work very well in some types of cancer, they show limited clinical efficacy in women with ovarian cancer with response rates of 10–15%.
One reason for these disappointing results may be OvCa’s unique tumor microenvironment (TME). The ovarian TME is characterized by large numbers of immune suppressor cells that inactivate the cancer fighting immune cells and inhibit the response of current immune therapy treatments. Despite this there are currently no approved therapies for targeting immune suppressor cells in the OvCa TME. We have discovered that EGFL6, a protein secreted by OvCa cells, induces tumor growth and drives an accumulation of immune suppressor cells in the tumor. We hypothesize that blocking EGFL6 will be an important therapeutic approach to prevent immune suppressor from entering the tumor and thereby enhance the efficacy of anti-tumor immune therapies. To test our hypothesis, we propose the following aims:
Specific Aim (1) To determine the molecular mechanisms by which EGFL6 controls proliferation, migration and differentiation of immune suppressor cells,
Specific Aim (2) To determine the immune-suppressive functions of EGFL6 within the tumor of mouse and human OvCa ascites and tumor tissues and
Specific Aim (3) To determine if therapeutics targeting EGFL6 will restore an active anti-tumor immune response. We will also determine if EGFL6 targeting therapy will act as an adjuvant to current immune therapeutic approaches.
IMPACT: These studies will evaluate a critical new target to enhance immune therapy. If successful, our studies could be translated into the clinic to improve the long-term survival of women with OvC.
Dr. Sandra Cascio is a Research Assistant Professor at the Magee-Womens Research Institute and the University of Pittsburgh's Department of OBGYN and Reproductive Sciences. She has received several prestigious national and international awards including the Ri.MED Foundation Grant, AIRC Fellowship, AACR-Scholar-in-Training Award and the Competitive Medical Research Fund Grant. Dr. Cascio obtained her PhD in Molecular Oncology from the University of Palermo (Italy) performing her thesis at Thomas Jefferson University (Philadelphia, PA) as Visiting Scholar. She studied the link between obesity and cancer, elucidating novel signaling pathways of leptin in breast and colon adenocarcinoma. During her post-doctoral training in the laboratory of Dr. Olivera Finn at the University of Pittsburgh she acquired expertise in tumor immunology developing a project focused on the crosstalk between tumor-associated macrophages and tumor epithelial cells. In 2019, Dr. Cascio joined Dr. Buckanovich’ group to study the cellular and molecular networks in the ovarian tumor microenvironment. Her research interests are centered on the molecular mechanisms that drive proliferation and differentiation of immunosuppressive myeloid cells and develop new strategies that will improve the efficacy of current immune checkpoint therapies in ovarian cancer.