Anat Erdreich-Epstein, MD, PhD

Pediatric high-grade gliomas are highly malignant brain tumors in children. Of these, Diffuse Midline Gliomas (DMG), including Diffuse Intrinsic Pontine Gliomas (DIPG), are especially deadly. Over 80% of these tumors carry a unique mutation that affects epigenetics, the chemical ‘marks’ on DNA that reversibly control the intensity of gene function. Our preliminary work discovered that an FDA-approved epigenetic drug used at low intermittent doses greatly prolongs survival of mice with such high-grade gliomas. Encouragingly, analysis of treated tumors shows that this drug exposes new vulnerabilities of the tumor to several potential therapies: we hypothesize these can be targeted by novel combination treatments together with this drug. Indeed, two reports in myeloid leukemia cell lines suggest that combining a novel drug called ONC201 with epigenetic modifying drugs has synergistic anti-tumor effect that is greater than each alone and greater than simply adding their effects. ONC201 is especially active in these mutated Diffuse Midline Gliomas and is currently in clinical trials. 

We propose to test combining ONC201 with the epigenetic drug in our unique biologically-faithful, molecularly-accurate, immune competent mouse glioma model via two Aims: Aim 1) To test in glioma cell culture and in our mouse glioma model the novel combination of ONC201 together with the epigenetic drug; Aim 2) To use a common MRI-based imaging method (MR spectroscopy) to define early treatment-induced metabolic changes in the mouse brain tumors, that can then serve as an early non-invasive sign of anti-tumor activity of this drug. Results of Aim 1, by demonstrating in our glioma-bearing mice the efficacy of combining the epigenetic drug with ONC201, will promote rapid translation of the treatment(s) into a pediatric clinical trial. Results of Aim 2 will be immediately implementable in clinical trials with these drugs, allowing to detect anti-tumor activity already a week or two after administration, which is long before tumor shrinkage can be evaluated. Our proposal, that is geared to develop novel approaches to therapy, will be ready for translation into clinical trials almost immediately after its results are obtained, thus rapidly helping advance the mission of PCRF, to fund research that will reduce the number of children who perish from cancer.