This proposal outlines a 5 year career development program designed to further my research program into the function and potential therapeutic utility of immune checkpoint molecules in the pediatric brain tumor, medulloblastoma (MB), the most common malignant brain tumor in children. As a pediatric neuro-oncologist, I am passionate about finding novel therapies for the ~25% of children whose tumors do not respond to standard treatment and have no cure. This proposal builds on my previous research evaluating the expression of PD-L1 in MB and generating a syngeneic animal model of MYC-driven anaplastic MB that mimics recurrent disease. I previously found that there was a paucity of PD-L1 expression in MB and thus far clinical trials of antibodies targeting this pathway have not met with significant success. Therefore, I moved my research program from Johns Hopkins University to Albert Einstein College of Medicine (AECOM)/Montefiore Medical Center (MMC) for the opportunity to work with my mentor, XingXing Zang, PhD on the novel B7 family immune checkpoint molecule, B7-H3, which is highly expressed in MB and represents an attractive therapeutic target. The scientific objective of this proposal is to evaluate the efficacy of B7-H3 blocking antibodies as a treatment for MB and lay the preclinical foundation for a future clinical trial. To accomplish this, I will study B7-H3 in my murine MB model as well as in classic human MB cell lines, and human MB patient samples. These studies stem from published literature reporting B7-H3 in human MB and my own preliminary data demonstrating its expression in my model. I will have strong support from my mentor, Dr. Zang, who has developed the translational B7-H3 blocking antibodies for this study as well as tools to knock down B7-H3 in the tumor and in the infiltrating immune cells. The purpose of this project is to both complete my scientific aims and to provide me with the additional knowledge and skills to launch a fully independent pediatric brain tumor research program. I will increase my immunology and neuroscience knowledge by participating in graduate courses and interacting with Dr. Zang an immunologist, and my co-mentor, Emad Eskandar, MD, a neuroscientist. I will obtain new skills important to the completion of this project that will also serve me in future research endeavors including the generation of bone marrow chimeric mice, and the analysis of single-cell RNA-seq data. I will participate in genomics and bioinformatics courses to familiarize myself with genomics techniques and learn the proper biostatistical methods to interpret them. These important skills will lay the foundation for my future an independent physician scientist.
This project will inform on the potential for using the immune checkpoint molecule, B7-H3, as a novel therapy for medulloblastoma, the most common malignant pediatric brain tumor. This will be accomplished by comprehensively evaluating its efficacy as a direct anti-tumor agent and as a modulator of the tumor immune microenvironment. This project will assess the ability of B7-H3 to penetrate the blood brain barrier and extend the survival of tumor-bearing mice while monitoring for any central nervous system toxicity.
