Ovarian cancer is the fifth leading cause of cancer-related death for women in the United States. High-grade serous ovarian cancer (HGSC) is the most lethal with 70% of patients succumbing to their disease within five years of diagnosis. The reasons for this poor survival are that there are currently no methods by which to detect HGSC early, and that there are limited therapies for HGSC beyond standard surgery and chemotherapy. The current HGSC chemotherapy regimen consists of two drugs that specifically target tumor cells. However, HGSCs are not just comprised of tumor cells. When we examine the makeup of a HGSC under the microscope, there is a network of tumor, connective tissue, and immune cells all mixed together. Thus, it is important to develop therapies which can impact each cell type in the tumor and not just tumor cells. With this idea in mind, scientists have generated a new type of therapy called an immune therapy which acts on the immune cells present in the tumor to spur them to attack and kill the tumor cells. These immune therapies are exciting because in other tumor types like skin, lung, colon, and even endometrial cancer, some patients are having good responses that prolong their survival. However, in ovarian cancer, despite many clinical trials testing multiple different immune therapies, these immune therapies have not had success in prolonging patient survival, leaving both scientists and physicians puzzled as to what is different about ovarian cancer. To understand why immune therapies have not worked in HGSC and to determine how to develop more effective immune therapies, it will be important to determine which immune cells are the best tumor cell killers and how to activate those cells in the tumor. To help achieve this, the Hill lab has generated a model of HGSC called a co-culture which contains matched patient tumor spheres, called organoids, and immune cells from the same tumor. The Hill lab is able to treat these co-cultures with immune or other therapy and then measure how the immune cells respond to the immune therapies using different readouts. In recent work testing immune therapies in these HGSC co-cultures, the Hill lab has identified a new immune therapy which can activate multiple immune cell types to kill tumor cells. This new therapy blocks the function of a protein called BRD1 in immune cells driving them into this tumor killing state. It is possible that this new therapy called a BRD1 inhibitor may be an effective immune therapy for ovarian cancer. However, beyond these preliminary results, little is known about what this BRD1 protein does in immune cells or ovarian cancer cells, and a deeper understanding is needed before this therapy can be used in the clinic. The goals of this proposal are to understand 1) what the BRD1 protein does in HGSC immune cells, and 2) how BRD1 inhibitors either alone or in combination with immune therapies excite immune cells to kill HGSC tumor cells. We will study how BRD1 controls immune cells and how BRD1 inhibitors work in HGSC using the Hill lab’s co-culture system and HGSC mouse models.
Zelei Yang, Ph.D., is a postdoctoral research fellow in Dr. Sarah Hill’s lab at Dana-Farber Cancer Institute. She obtained her B.S. (Honors) in Biochemistry from University of Alberta, Canada. She then completed her Ph.D. in Biochemistry at University of Alberta, under the co-supervision of Dr. David Brindley and Dr. Denise Hemmings. Her Ph.D. thesis certified that latent cytomegalovirus infection enhances breast cancer metastasis in mouse models. Further investigation showed that human cytomegalovirus (HCMV) preferentially infects fibroblasts and platelet-derived growth factor receptor-a expressing breast cancer cells. Significantly, HCMV infection in the tumor microenvironment, rather than breast cancer cells, will increase the inflammatory milieu that could enhance metastasis. Dr. Yang received several fellowships during her graduate study, including a Dean’s Doctoral Student Award and a Queen Elizabeth II Graduate Studentship.
At Dana-Farber Cancer Institute, Dr. Yang continues to explore the tumor microenvironment in women’s cancers, specifically studying mechanisms of overcoming immune cell dysfunction in high grade serous ovarian cancer (HGSC). Her research for this OCRA award focuses on deciphering the mechanism of action of the bromodomain-containing protein BRD1 in intra-tumoral immune cells, and how inhibition of BRD1 alone or in combination with other immune therapies may re-engage the anti-tumor immune response against ovarian cancer. In the long-term, this may lead to new immune therapies which have the potential to help all ovarian cancer patients. This OCRA Ann and Sol Schreiber Mentored Investigator Award will give Dr. Yang protected time for this clinically important research and hopefully help her provide more effective immune therapies for HGSC patients.