Dependency of H3K27M-Mutated DIPG on BMI1-Mediated Cell Self-Renewal
Abstract
Topic Area and Military Relevance: The Fiscal Year 2016 Peer Reviewed Cancer Research Program newly added pediatric brain tumors as one of the topic areas for funding. The review of this topic area shows the focus on pediatric tumors and medical conditions with an especially strong negative impact on patients, which is certainly true for pediatric brain tumors and their families. The proposed research addresses the critical and immediate need for the development of new therapy strategies for the worst pediatric brain tumor patients. Scientific Objective: Our research addresses the critical and immediate need for the development of a new therapy for diffuse intrinsic pontine glioma (DIPG). DIPG is a pediatric brain tumor of the brain stem with a survival rate of 0% and a median survival from diagnosis of 10 months. The location of the tumor makes it inoperable. Therapy consists of radiation that provides only temporary relief. DIPG affects school-going kids globally between the age of 4 and 11 years old. New research has identified genetic mutations in DIPG tumors. Unfortunately, the genetic data have not yet resulted in a new, better therapeutic option. The majority of patients have mutations in histone genes. We hypothesized that additional genes that are abnormally regulated in this tumor are critical for tumor growth. To examine this, we targeted 410 genes that are critical to developmental regulation by epigenetic mechanisms using advanced genomic tools. We found one specific developmental stem cell factor, BMI1, which was critical for DIPG cell survival. Our working model is that BMI1 drives DIPG tumorigenesis by promoting self-renewal of tumor stem cells and driving resistance to radiation therapy. Our goal is to find an effective drug that inhibits this BMI1 gene activity and thereby sensitize the DIPG tumors to radiation and to find a cure. Excitingly, a new chemical inhibitor of BMI1, PTC-209, that suppressed colon cancer stem cells and thereby suppressed colon cancer growth was recently reported. Our initial data show that both the genetic and pharmacological inhibition of BMI1 suppresses DIPG cell growth and increases sensitivity to radiation. We now plan to carefully exam how BMI1 cooperates with mutations in DIPG and whether chemical inhibition of BMI1 can suppress tumor growth in animal models of DIPG. Ultimate Application of the Research: The findings from this research proposal will define the role of BMI1 in DIPG and establish how it collaborates with various genetic mutations that occur in this aggressive tumor. Our study will establish BMI1 as a target for enhancing radiation therapy in DIPG. In addition, since drug penetration into pons is being a biggest challenge in finding new therapeutic models in DIPG, our study could highlight the use of non-traditional chemotherapeutic drugs for DIPG tumor for radio-sensitization and treatment. How Will This Research Help Service Members and Families? This research has the potential to help a broad range of Service members and their families. DIPG is an aggressive brain tumor found in young school-going kids, and our research mainly applies to pediatric population. This is the worst life-threatening brain tumor with 0% survival compared to other pediatric and adult brain tumors. A life-threatening illness in a child can have a destructive effect on the whole family. Our study can improve the care of these patients both by increasing their chance of survival and decreasing the long-term effect of radiation, which is the only current palliative therapy for these patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710366
Entities
People
- Sujatha Venkataraman
Organizations
- United States Army
- University of Colorado Denver