THERAPEUTIC TARGETING OF NOTCH IN OVARIAN CANCER

Career Development PlanThe overall career goal of Dr. Wright is to become an independent clinician scientist with a focus on ovarian cancer researcher. The major emphasis of Dr. Wright's work is on understanding the molecular mechanisms of ovarian carcinogenesis and the development of novel therapeutic approaches for the treatment of the disease. Dr. Wright has a strong commitment to becoming an independent ovarian cancer researcher as demonstrated by his academic record as well as his protected research time. As such, Dr. Wright is uniquely posed to undertake the proposed research, and his overall career goals coincide well with the tenets of the Department of Defense application. This 3-year career development grant will afford Dr. Wright the opportunity to receive additional training in ovarian cancer research, expand his knowledge of tumor angiogenesis, and allow him to complete mentored research work that will lead to the submission of future independent proposals. This award will therefore have an important effect upon the development of Dr. Wright's research career as an independent clinician scientist.Research PlanBackground: The Notch signaling pathway represents a critical component in cell fate determination during embryonic development. The Notch proteins are a family of highly conserved transmembrane proteins that consists of four receptors and five ligands. In addition to their classic role in cell fate determination, the Notch proteins also enhance cell survival and proliferation and promote angiogenesis. Most importantly, Notch signaling has been implicated in the development of a number of human malignancies including ovarian cancer.Objective: The Notch proteins, particularly Notch1 and Notch3, appear to play important roles in ovarian carcinogenesis. The overall goal of this work is to determine the functional significance of Notch in ovarian cancer and examine the therapeutic potential of inhibiting various portions of the Notch signaling cascade.Specific Aims: The specific aims of this proposal will examine the expression of the Notch pathway in ovarian cancer and determine the effect of blocking Notch1 and Notch3 signaling.Study Design: In the initial phase of this proposal, we will comprehensively determine the patterns of expression of the four Notch receptors and five Notch ligands in ovarian cancer. This work will be performed on ovarian cancer tissue obtained from a large cohort of women collected prospectively across the United States. We will then examine the functional consequences of inhibiting Notch signaling. These experiments will rely on novel Notch decoy receptors that have been developed and validated in our laboratory. We will perform cell line and ovarian cancer xenograft experiments. In one set of experiments, we will determine the effect of inhibiting Notch1 with our Notch1 decoy. This work will be performed in a nude mouse model of ovarian cancer. Mice that receive the Notch1 receptor decoy will be compared to a similar group of controls. Preliminary results from our group suggest that the Notch1 receptor decoy inhibits tumor growth in ovarian cancer. A similar set of ovarian cancer cell line and xenograft experiments will be performed to examine the consequences of Notch3 inhibition with our Notch3 decoy. In addition to directly evaluating tumor growth, we will determine the molecular underpinnings associated with Notch blockade in ovarian cancer. Notch inhibition may directly affect tumor cell growth, angiogenesis, or a combination of the two. A thorough exploration of the effects of Notch on proliferation, apoptosis, oncogenic signaling, and angiogenesis will be performed. Finally, we will evaluate the Notch1 and Notch3 receptor decoys in combination with traditional cytotoxic chemotherapeutic agents.Impact: This work represents the first large-scale evaluation of the role of Notch in ovarian cancer. In addition to gaining an understanding of the patterns of expression of Notch in ovarian cancer, we will directly examine the effect of inhibiting Notch signaling at various stages of ovarian cancer development and progression. If successful, this work will serve as proof of principle for the development of Notch inhibitors into clinical trials.