Novel Targeting of a Cell Surface Protein, CD99, in H3K27M-Mutated DIPG
Abstract
The Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Area and Military Relevance: The FY19 PRCRP recently added pediatric brain tumors as one of the priority topic areas for funding. Recent posts from Health and Washington magazines declared brain cancer as the leading cause of cancer in kids, which indicates that a disheartening number of children and their families will be faced with difficult challenges. Within the types of pediatric brain tumors, diffuse intrinsic pontine gliomas (DIPG) are particularly devastating, as the cancer is currently untreatable and median survival from diagnosis is only 10 months. The location of the tumor makes it inoperable, and therapy consists solely of radiation that provides only temporary relief. This proposal addresses the critical and immediate need for the development of new therapeutic strategies for children diagnosed with DIPG. Scientific Objective: New research has identified genetic mutations in DIPG tumors, particularly affecting histone genes, which may provide new opportunities to develop novel treatments. We found that one specific cell surface protein, CD99, is expressed at very high levels in DIPG patient tumors and in cell lines harboring a histone H3K27M mutation. CD99 was first found to be highly expressed in Ewing Sarcoma (EWS), a rare cancer seen in teenagers and young adults. Researchers showed that blocking CD99 activity blocked the growth of EWS tumor in preclinical models. Our initial experiments performed in DIPG showed that blockade of CD99 reduced cell proliferation and cell stem-ness, suggesting an oncogenic role for CD99 in DIPG. Our working hypothesis is that histone mutations lead to CD99 overexpression, which drives DIPG tumorigenesis by promoting self-renewal of tumor stem cells and causes resistance to radiation therapy. Excitingly, our pilot in vivo studies in mouse DIPG brain tumor model suggest that the CD99 (0662) antibody, when administered intravenously, can cross the blood-brain barrier with no evident toxicity to the normal cells. We will more thoroughly study the effect of administering CD99 antibody on DIPG tumor growth inhibition. We now plan to carefully exam how CD99 co-operates with mutations in DIPG and understand the mechanism of CD99 associated DIPG tumorigenesis. Ultimate Application of the Research: The findings from this research proposal will define the role of CD99 in DIPG and establish how it collaborates with various genetic mutations that occur in this aggressive tumor. Recently, an article on the “expert opinion on therapeutic targets” by Tavakkaoli, et al., recommended anti-CD99 antibody as a promising therapy for hematologic malignancies. Our study will establish CD99 as a therapeutic target in the brain tumor, DIPG. In addition, drug penetration into the pons is a major challenge in treating DIPG. The use of antibodies against CD99 to target DIPG tumorigenesis is novel and will be a dramatic shift in the treatment paradigm for this refractory brain tumor. This study will lead to an improved understanding of the genetic drivers in DIPG and their association with cell surface proteins to drive tumorigenesis and identifying immuno-oncology approach to treat a currently incurable brain tumor in children. How will this research help Service members and families? This research has the potential to help Service members should they ever be confronted with a diagnosis of pediatric brain cancer in their family. DIPG is an especially aggressive and frightening brain tumor and worse – it affects young school-age kids. Even the possibility of a brain cancer diagnosis is overwhelming, and the knowledge that effective treatments are available will benefit everyone. Moreover, a life-threatening illness in a child can have a destructive effect on the whole family. Our study can improve the well-being of these patients their entire family by increasing the chance of survival and decreasing the long-term effe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010604
Entities
People
- Sujatha Venkataraman
Organizations
- United States Army
- University of Colorado Denver