Interrogation of the KDM1A-IL18 Axis in Pediatric High-Grade Glioma
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a type of brain cancer in children that is currently incurable. The median survival is less than 1 year from diagnosis, and it has not improved in over 50 years. The tumor is located in the brainstem, a part of the brain which controls important body functions like breathing, precluding surgical removal. Radiation treatment remains the standard of care for DIPG. Despite hundreds of clinical trials, no drug has increased the survival of children with DIPG, highlighting the critical need to develop new and effective therapies. In the past decade, there has been an increased effort to harness the power of the immune system against cancer. While there has been some success for immunotherapy against some types of cancer, this has yet to be realized for pediatric high-grade gliomas. Nonetheless, there is an ongoing effort to harness the power of the immune system against pediatric high-grade gliomas. This is evident by the fact that one-third of clinical trials that are currently enrolling patients with DIPG are immunotherapy trials. However, one major knowledge gap preventing success is an in-depth understanding of how DIPG tumor cells evade the immune system. Recently, we have observed that a protein called LSD1, or KDM1A, inhibits the expression of immune-related genes such as IL18 in DIPG. In this study, we propose to study the mechanisms by which LSD1 contributes to DIPG progression, focusing on its effects in modulating the immune system, specifically IL18. We will delete and overexpress LSD1 in DIPG cells and evaluate the effects on DIPG growth and survival. In addition, in order to unravel the effects of LSD1 deletion or overexpression on stromal cells (cells present in the tumor that are not tumor cells), we will use single-cell RNAseq, a new technique that allows one to unravel which genes are upregulated or repressed by LSD1, genetic, or pharmacological manipulation in a cell-type specific manner. To accomplish our research goals we will use two types of mouse models: (1) genetic models that carry gene mutations that are specific to and occur in the majority of DIPG patients, and (2) human models where tumor cells obtained from patients are transplanted into mouse brains. As we have data indicating that LSD1 inhibition affects the expression of immune related genes, it is important to perform these experiments in genetic models, which harbor an intact immune system. We believe that rigorous testing of novel therapies in both types of models is essential to identifying treatments that will work effectively in patients. This project will be a collaborative effort between two investigators with complementary expertise – a physician-scientist with expertise in studying DIPG growth and treatment using genetic models, and a scientist with expertise in studying human models and utilizing LSD1 inhibitors to treat brain tumors. Several LSD1 inhibitors are currently in clinical trials for other types of cancer, but they have not been tested in DIPG before. We expect that, by the end of this award period, we will gain an improved understanding on the role LSD1 plays in the regulation of the immune system in pediatric high-grade gliomas, elucidate the role of IL18 in gliomagenesis, and identify the most effective LSD1 inhibitor to treat DIPG, with a plan to start a clinical trial for children with pediatric high-grade gliomas at the end of the award period. Because families of military personnel suffer a higher risk of brain tumors than the general public, our study addresses at least four Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Areas as directed by Congress (Pediatric Brain Tumors; Brain Cancer; Immunotherapy; and Cancer in Children, Adolescents, and Young Adults). DIPG is among the most difficult to treat pediatric tumors; therefore, any significant therapeutic advancement in DIPG will likely be applicable to other types of cancer as well.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110728
Entities
People
- Oren Becher
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army