Our research is focused on targeting the glucose metabolism of ovarian cancer. We are developing imaging based treatment strategies to guide and optimize the inhibition of metabolic pathways. As proof of concept, we will inhibit three targets within the glycolytic pathway: a) the glucose transport into cells by inhibiting glucose transporter (Glut) proteins b) the phosphorylation of glucose to glucose-6-phosphate by inhibiting hexokinase-2 (HK-2), and c) the inhibition of phosphofructokinase-2 (PFK-2). CG-5 binds and inhibits the activity of transmembrane glucose transporter; Lonidamine targets mitochondrially-bound HK-2; and 3PO inhibits PFK-2. Positron emission tomography (PET) using [F-18]Fluorodoxyglucose ([F-18]-2-FDG) allows for noninvasive imaging of tumor glucose uptake. In addition, we will use a novel agent [F-18]-6-FDG, which is established in our labs and, as a non-phosphorylated glucose analog, provides mechanistic data specifically about the transport of glucose through the cell membrane. A significant challenge is to define and quantify metabolic responses to glycolytic pathway inhibition, for which we will develop and validate appropriate PET kinetic models in vivo. Therefore we will: a) Target ovarian cancer by specific inhibition of the glycolytic pathway in vitro; b) Perform [F-18]FDG microPET/CT imaging in ovarian cancer bearing animals during the inhibition of the glycolytic pathway; and c) Develop and validate kinetic models for analysis of [F-18]FDG in vivo. With the successful completion of these aims we will have developed PET analysis approaches for different mechanisms inhibiting the glycolytic pathway, which is important to guide and optimize their future use.
Epithelial ovarian cancer is one of the most common gynecologic malignancies often presenting with advanced stages of disease with tumor spread to the abdominal cavity. The standard systemic treatment includes the cytotoxic drug cisplatin combined with taxanes; however, approximately 80% of patients will relapse after first-line platinum-based chemotherapy resulting in a limited overall survival. The goal is to inhibit specifi targets within the upregulated glycolytic pathway in ovarian cancer and develop methods for noninvasive PET imaging to describe specific steps within the distribution, transport, and phosphorylation of glucose using [F-18]-2-FDG. With the successful completion of this research project we will have developed PET analysis approaches for different mechanisms inhibiting the glycolytic pathway, which is important to guide and optimize their future use in patients.
