Yap1 Function in Sex-Biased Medulloblastoma Tumorigenesis, Progression, and Protumor Immunity
Abstract
I plan on pursuing a career in academia, particularly pediatric brain cancer research. My long-term goal is to decode key players in the immune microenvironment of pediatric brain tumors. The Peer Reviewed Cancer Research Program (PRCRP) Horizon Award will pave the way for outstanding and crucial training for me to become an independent and comprehensive cancer researcher, as well as help discover new druggable targets in this important field. I am currently training as a postdoctoral fellow under Dr. Kyuson Yun’s mentorship. I am learning from her extensive expertise in brain tumor biology, brain cancer stem cells, and mouse models. Medulloblastoma is the most common pediatric solid malignant tumor in children. More than 70% of medulloblastoma occurs in children below the age of 10. Medulloblastoma is more common in males (about 62%) than females (about 38%), and currently we do not understand what contributes to this sex-bias. Medulloblastoma is treated with surgery, radiation, and chemotherapy, which are very harmful to developing brains. Even with these aggressive treatments, about 30% of medulloblastomas are incurable. Children who survive the disease suffer from devastating and life altering long-term side effects. Immunotherapies, utilizing one’s own immune system to combat cancer, have tremendous potential to provide durable therapeutic benefit while minimizing side effects. Therefore, immunotherapies are particularly appealing for pediatric cancer patients. However, the immunologic landscape of medulloblastoma remains poorly understood, and currently, there are no effective immunotherapies for pediatric brain tumors. In the proposed study, we will examine the novel role of Yap1, an important gene in cancer formation, in the recruitment of immune cells into medulloblastomas. Our preclinical data show that deleting YAP1 can prevent medulloblastoma in about 40% of SHH mouse models. Interestingly, this effect of blocking medulloblastoma formation is stronger in male mice than in female mice. Moreover, Yap1 deletion increased the recruitment of immune cells into the brains of rescued animals. These results suggest that Yap1 plays a role in immune recruitment to brain cancer, and in addition, it might partially explain the sex bias in medulloblastoma incidence. Currently, there are on-going efforts in industry and academia to develop Yap1 inhibitors as anti-cancer therapy (including the Yun laboratory). Results of this study will determine the potential use of such inhibitors as immune modulators in the treatment of medulloblastomas. Medulloblastoma accounts for about 20% of pediatric brain tumors and affects 250 to 500 children every year including children born to military families. Thus, results of the proposed research will directly benefit military personnel and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010599
Entities
People
- Nourhan Abdelfattah
Organizations
- Houston Methodist Research Institute
- United States Army