Ovarian cancer (OvCa) is the deadliest US gynecologic malignancy with a clear need for novel therapeutic approaches. Immunotherapy, a class of treatments that restores the patient’s immune system to recognize and kill cancer cells, is one promising approach to improve the outcome of OvCa patients. While current immune therapies work very well in some types of cancer, they show limited clinical efficacy in women with ovarian cancer with response rates of 10–15%. One reason for these disappointing results may be OvCa’s unique tumor microenvironment (TME). We recently demonstrated a population of cells in the OvCa TME, known as a carcinoma associated mesenchymal stem cells (CA-MSCs), are driving the poor response to immune therapy. CA-MSC create dense scar tissue around islands of cancer cells, and recruit populations of immune-suppressing macrophages to the scar tissue. This macrophage laden scar tissue prevents cancer fighting immune cells from entering the tumor. Importantly we found that targeting this CA-MSC/macrophage axis can overcome this immune-suppressive barrier and allow immunotherapy mediated tumor eradication. These studies suggested a poorly studied macrophage factor, BIGH3, may be driving the immune-suppression of CA-MSCs. We found that BIGH3 directly inactivates the anti-cancer activity of a critical population of cells know as NK cells. Furthermore, high BIGH3 expression is associated with shortened patient surivival and poor response to immune therapy. We hypothesize that BIGH3 is a critical suppressor of anti-tumor immunity in ovarian cancer, restricting the entry anti-tumor immune cells into the tumor, thereby inhibiting the response to immune therapy. As an extension of this, we postulate that blocking BIGH3, will be an important therapeutic approach to enhance the efficacy of anti-tumor immune therapies. To test our hypothesis, we propose the following aims: Specific Aim (1): To determine the molecular mechanisms by which BIGH3, secreted by monocytes and macrophages, blocks the tumor killing activities of NK cells. Specific Aim (2): To determine if therapeutics targeting BIGH3 will restore an active anti-tumor immune response. We will develop a new antibody therapy targeting BIGH3 and determine if BIGH3 blocking antibody will act as an adjuvant to current immune therapeutic approaches. IMPACT: Based on the success of the first three years of support for our work, we will initiate a new clinical trial to improve ovarian cancer patient response to immune therapy (planned to start spring 2022).These new studies studies will generate a new putative therapeutic antibody targeting BIGH3 as a critical new target to enhance immune therapy. If successful, our studies will add to ongoing approach to improve the benefits of immune therapy for ovarian cancer patients.
Professor of Medicine Director of the Ovarian Cancer Center of Excellence Co-Director of the Womens Cancer Research Center Magee-Womens Research Institute UPMC Hillman Cancer Center University of PittsburghRonald Buckanovich graduated from Cornell University in 1990 with a B.S. in Genetics and Biochemistry. He then completed the Medical Scientist Training Program and started his life-long study of ovarian cancer. He received his Ph.D. in 1996 from the Rockefeller University and his M.D. in 1998 from Cornell University. Dr. Buckanovich then went on to complete an Internal Medicine residency and a Hematology-Oncology fellowship at the Hospital of the University of Pennsylvania. During his fellowship he continued his research on ovarian cancer, identifying dozens of novel clinical targets and helped to develop a novel therapeutic to enhance tumor vaccine therapy. Dr. Buckanovich joined the University of Michigan as ascended to the ranks of Associate Professor. There he also served an associate director for the Hematology Oncology Fellowship. In 2017 Dr. Buckanovich was recruited to the Magee Women’s Research Institute and UPMC Hillman Cancer Center of the University of Pittsburgh as a Professor of Medicine and serves as the Director of Ovarian Cancer Center of Excellence and Co-Director of the Women’s Cancer Research Center. His lab has identified a novel population of cancer stem-like cells (CSCs) which may be responsible for ovarian cancer metastasis, chemotherapy resistance and ultimately disease recurrence. His laboratory also identified and characterized a novel population of cancer associated mesenchymal stem cells (MSCs)—normal cells recruited by the cancer to help the cancer grow. His laboratory is now studying the factors which regulate CSCs and MSCs including regulators of asymmetric division and quiescence. His laboratory work has resulted in the initiation of 4 translational clinical trials for the treatment of ovarian cancer. In addition, his group has identified two novel compounds which are now being developed for first in human clinical trials; one which blocks the ability of cancer cells to metastasize, and a second which selectively kills the cancer stem-like cells to reverse chemotherapy resistance. Based on the knowledge he has gained studying the tumor microenvironment, his group is now also looking at ways to enhance anti-tumor immune therapy by targeting host cells in the tumor. In addition to his laboratory studies, Dr. Buckanovich has a busy clinical practice, specializing in the treatment of ovarian and uterine cancers. He is currently the principal investigator of two clinical trials at the University of Pittsburgh. He has been an author or co-author of 70 original research articles. In recognition of his work, Dr. Buckanovich received a Clinical Investigator Award from the Damon Runyon Cancer Research Foundation, the National Institutes of Health New Innovator – Directors Award, Society of Gynecologic Oncology Best Basic Science Award, and he has been elected to the American Society of Clinical Investigators.