The Role of EGFR and FOXG1 in Diffuse Midline Glioma Response to Mitochondrial-Targeting Drugs
Abstract
Brain tumors are now contributing to the most cancer-related deaths in children. One of the deadliest tumors we face within pediatric neuro-oncology are diffuse midline gliomas (DMG). Over 2,000 children and young adults are diagnosed with these tumors in the United States and Europe every year. Despite decades of research, outcomes remain poor, and essentially all children die less than 2 years from being diagnosed. Over the last several years however, we made great progress in understanding much more about the biology of these tumors. We now understand that, although these tumors have a similar presentation and age of onset, the biology of tumor may vary from patient to patient. In other words, a DMG lesion that occurs in brainstem may be biologically different than a DMG that occurs in thalamus. In our proposal we aim to understand how these differences within the tumor and also the surroundings structures of these tumors – often referred to as the tumor microenvironment – impact response to therapies. Specifically, within the proposed research we are examining the response to a novel agent named ONC201 and its derivatives (sister compounds such as ONC206). ONC201 is given by mouth and belongs to a new class of medicines that targets and impairs tumors energy supply. We used ONC201 in the clinic to treat DMG patients that carry histone mutation (H3K27M, which occurs in 70% of DMGs). We found that ONC201 leads to a near doubling of progression-free survival and overall survival in some DMG sub-groups as well as improvements in the MRI appearance of tumors that persist for over 2 years (total number of patients analyzed=50). The most notable and durable responses are found in DMG patients with thalamic tumors and in those treated post-radiation and who did not show any sign of tumor growth. This difference in response might be due to specific characteristics of the tumor itself or due to differences in the tumor microenvironment. Our studies found two proteins (FOXG1 and EGFR) that may play a role in tumor resistance to ONC201. We focus on these two proteins because our preliminary data examining over 500 human cancer cell lines, as well as specimens from the ongoing clinical trial, show that these two proteins play an important role in response to ONC201. The overall goal of our research project is to understand how these proteins might alter tumor response to ONC201 treatment. To test our hypothesis, we will use brains (donated from families at time of death) from patients who received ONC201 and compare results to brains from patients who did not receive ONC201. We will use state of the art genomic profiling to look for differences, with a focus on EGFR and FOXG1. Further, we will use DMG cell lines that we developed in our laboratories to either diminish or enhance the presence of EGFR and FOXG1 and assess if the presence or absence of these two proteins will change the response to ONC201. Further, we will assess EGFR and FOXG1 expression in DMG samples that will be collected as part of a clinical trial and correlate these with clinical response. At the end of our research project we will have determined which patients will best respond to ONC201 and therefore, significantly enhance the therapeutic benefit. Further, understanding the mechanism of resistance to such therapy will allow us to develop combination strategies that might enhance the effectiveness. The proposed research directly addresses the Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of Pediatric Brain Tumors and aims to understand treatment responses to an exciting new therapy. Thus, this proposal addresses a critical gap in cancer treatment that affects the well-being of military members, Veterans, their beneficiaries, and the general public. The team consists of three partnering investigators with complementary expertise and two Co-Investigators. Dr. Nazarian is an expert in DMG preclinical model develop
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110723
Entities
People
- Carl Koschmann
Organizations
- United States Army
- University of Michigan