Ovarian cancer is the 5th leading causes of cancer death among women in the United States. This disease is often detected at late stages after peritoneal metastasis, at which point prognosis is poor. Standard therapy includes combination platinum and taxane chemotherapy following the surgical resection of tumors. Unfortunately, ovarian tumors frequently present with or develop resistance to current chemotherapeutic regimens, and this drug resistance represents a major hurdle in the treatment of disease. The goal of this proposed research is to better understand how to target ovarian cancer and potentially impact clinical outcomes. The role of the Notch signaling pathway in the development of chemo-resistance in ovarian cancer will be explored. Notch signaling is characterized by juxtacrine interactions between Notch receptors and ligands on adjacent cells, and is known to play a role in many aspects of tumorigenesis. The Notch3 receptor is upregulated in ovarian cancer and is correlated with both worse prognosis and chemotherapy resistance. The effect of Notch3 activation in vitro will be assessed with a cytotoxicity assay to determine the dose response to cisplatinum therapy. A mouse model of ovarian cancer will also be used to determine if Notch3 activation in metastatic ovarian cancer will increase platinum resistance. In addition, studies will be performed to determine if the use of a novel Notch3 inhibitor is capable of reducing chemotherapy resistance in a metastatic ovarian cancer model. This will be the first study defining intraperitoneal metastatic ovarian growth with use of combination platinum and Notch inhibitor therapy using non-toxic Notch3-specific inhibition. In addition to its role in endogenous tumor signaling, Notch plays an important role in the establishment of tumor vasculature. Angiogenesis, the development of new blood vessel from pre-existing vessels, is important in the development of ovarian cancer. Angiogenesis contributes to tumor cell survival and ascites accumulation. Notch1 signaling is required to produce functional tumor vasculature, and its inhibition is known to disrupt vasculature function. The effect endothelial-specific knock out of Notch1 on tumor vasculature will be assessed in a metastatic mouse model of ovarian cancer. These experiments will elucidate the effect of Notch1 signaling in the vasculature on the growth and development of ovarian cancer. Furthermore, the effect of a novel, proprietary Notch1 inhibitor on the development of ovarian cancer and the resultant tumor vasculature will be examined. These studies will generate insights into the utility of Notch inhibition in the treatment for aggressive ovarian cancers.
Ovarian cancer is the most fatal gynecologic malignancy because it is detected at late stages and frequently becomes resistant to chemotherapy. The Notch signaling pathway is a potential therapeutic target since it has been correlated with more aggressive ovarian cancers, correlated with chemotherapy resistance, and is involved in the development of blood vessels necessary for tumors to thrive. Therefore Notch signaling is a promising target in ovarian cancers, and may help reduce the fatality of this aggressive cancer.
