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Improving Immune Response in Ovarian Cancer by Modulating the Wnt Pathway


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Even though 80 percent of ovarian cancer patients will achieve a complete remission with a combination of surgery and chemotherapy, almost all will recur due to the development of chemoresistance. The WNT/beta-catenin pathway is involved in ovarian cancer growth and suppressing the ability of the immune system to fight off the cancer. Many ovarian cancers have a deficiency in the ability to repair its own DNA, called DNA repair deficiency. Recent clinical efforts have focused on using immune-directed therapies for the treatment of cancer, and specifically ovarian cancer. Although only a small subset of ovarian cancer patients respond to immunotherapy. Our goal to gain a better understanding of how DNA repair deficiency and upregulation of the WNT/beta-catenin pathway effect immune response and patient outcomes in ovarian cancer. Our preliminary data show that using a WNT inhibitor for the treatment of ovarian cancer in a mouse model improves the immune systems ability to fight off the cancer. Our central hypothesis is that inhibition of the WNT/beta-catenin signaling pathway will promote antitumor immune response and repress tumor growth, thereby improving clinical response. WNT/beta-catenin genes regulate cell proliferation, thereby mediating cancer initiation and progression and we have successfully targeted this pathway in cells isolated from patients with ovarian cancer and shown that a WNT inhibitor downregulates the WNT pathway and, in a subset of patient samples, caused cell kill. This project will examine the inhibition of the WNT/beta-catenin pathway using a mouse model of spontaneously developing ovarian cancer. In addition, we will also implant ovarian cancer cells with and without DNA repair deficiency into mice that have an intact immune system. The specific aims of this project are: 1) To determine the relationship between WNT/beta-catenin signaling, the DNA repair pathway, T cell responses and clinical outcomes in ovarian cancer.



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