Improving Immune Response in Ovarian Cancer by Modulating the Wnt Pathway
Abstract
Even though 80% 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 is 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 system’s ability to fight off the cancer. Our central hypothesis is that inhibition of the WNT/beta-catenin signaling pathway will promote anti-tumor 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. (2) To determine how inactivation of the WNT pathway by the tumor and dendritic immune cells impacts T cell responses and tumor growth using mouse models. (3) To determine whether mutations that affect DNA repair impact T cell responses following treatment with WNT inhibitors. The proposed research is significant because it will investigate the role of WNT-mediated T cell exclusion from the tumor and elucidate the therapeutic potential of novel WNT inhibitors against ovarian cancer cells with and without a mutation that causes deficiency in the DNA damage repair mechanism. My ultimate career goal is to establish myself as a clinician-scientist performing translational research that positively impacts the lives of ovarian cancer patients. With strong mentorship and collaborations, I expect that I will build an outstanding, interdisciplinary translational research program at UAB and that my participation in the OCRP Ovarian Cancer Academy will aid me in becoming a successful, highly productive ovarian cancer researcher. This proposal has many characteristics important for an early investigator: It addresses unanswered questions in treating ovarian cancer, it has achievable goals with focused endpoints, it has the potential to be translated into future clinical studies, and it will generate a wealth of new data and ideas to support future proposals for independent funding. The OCRP Ovarian Cancer Academy has a strong history of funding investigators that develop successful careers as physician scientists and leaders in gynecologic oncology. The Academy will allow me to interact with other awardees, mentors, and leaders in the field to exchange ideas and form new collaborations. This proposed study is highly translational and will form preliminary data that can be further expanded upon as the basis for future clinical trials for patients with ovarian cancer within the next 4 years. Military Service members and other military beneficiaries will continue to have friends
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810231
Entities
People
- Rebecca C Arend
Organizations
- United States Army
- University of Alabama at Birmingham