Diala Ajaero
Pronouns: He/Him
Research Mentor(s): Robert Doherty
Research Mentor School/College/Department: Pediatrics / Medicine
Program:
Authors: Diala Ajaero, Benison Lau, Carl Koschmann
Session: Session 2: 10:00 am – 10:50 am
Poster: 30
Abstract
Introduction/Background Children and young adults with diffuse midline glioma (DMG) harboring the H3K27M mutation rarely survive longer than two years. DMGs form in distinct locations (such brainstem and thalamus) and 70% carry a mutation in the histone H3F3A (H3K27M) which confers a worse prognosis. DMG also known as DIPG is an aggressive pediatric brain tumor median survival rate, of which only 10% of affected youth surviving past 2 years. Recently the Koschmann lab uncovered that ONC201 is particularly effective in H3K27M mutant-DMG and has demonstrated that ONC201 is the first monotherapy to improve outcomes in H3K27M-DMG beyond radiation, nearly doubling overall median survival. ONC201 has been shown to activate the mitochondrial protease ClpP resulting in mitochondrial-mediated cell death in cancer cells dependent on oxidative phosphorylation. Despite this impressive efficacy in H3K27M-DMG, ONC201 is not curative, and does not lead to clinical or radiographic responses in 60% of patients. We do not know how to predict which H3K27M-DMG patients will be responders to ONC201, and traditional clinical MRI results are ambiguous or delayed in demonstrating tumor progression. Methods Noninvasive imaging with multi-contrast magnetic resonance imaging (MRI) remains the standard for response assessment in DMG. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group proposed specific imaging protocols, MR sequences and response categories based on depending on the percent change in the 2D area in a single plane. Standardized procedure for measurement involves 2D segmentation; in this sphere, we wish to attempt to improve the accuracy of measurement by evaluating the tumor on a 3D plane which we wish to see will show improved accuracy as it relates to the previous form of measurement. Perfusion imaging helps to assess the hemodynamics within an anatomical area, as such it can create maps demonstrating cerebral blood volume (CBV volume fraction of vascularized tissue, vascularized), cerebral blood flow (CBF; the volume of blood flow per minute). We hypothesize that decreases in cerebral blood volume will positively correlate with ONC201 responsiveness and correlate with prolonged PFS preceding anatomic changes on traditional imaging. Diffusion-weighted images are also important in neuro-oncology. DWI’s provide information on the diffusivity of water on the cellular level that tumors depend on, ADC imaging is one method of viewing this; with DWI’s allowing professionals to determine the tumor grade and type, while other imaging techniques are used generally for mass evaluation of tumors. One problem with DWI however, is that tumors tend to spread into edema, and finding the tumors’ borders within the edema considering the contrast that edema showcases in scans can be challenging. We also hypothesize that a potential decrease in ADC will correlate with ONC201 responsiveness in terms of increased survival. Expected Result Our research project focuses on investigating quantitative measures on MRI as a predictive tool for assessing the efficacy of ONC201 treatment in children and young adults diagnosed with diffuse midline glioma (DMG) harboring the H3K27M mutation. This project aims to address this gap by exploring perfusion and diffuse weighted imaging as a potential predictive biomarker for treatment responsiveness. The comprehensive study involves a multimodal analysis performed by an interdisciplinary team of neuro-oncology, radiology and radiation oncology research and a detailed longitudinal assessment of approximately 60 patients treated with ONC201 at the University of Michigan. We hypothesize that decreases in cerebral blood volume will positively correlate with ONC201 responsiveness and correlate with prolonged PFS preceding anatomic changes on traditional imaging. Our approach encompasses routine longitudinal, multi-sequence MRI imaging. We will review clinical data from patients treated with ONC201 at a tertiary medical center. Imaging will first undergo consensus review by two expert neuroradiologists utilizing the Response Assessment in Pediatric Neuro-Oncology (RAPNO) grading. Volumetric segmentation will be performed using semi-automated techniques based on thresholding, providing a nuanced understanding of the tumor’s spatio-temporal profile during treatment. We will use the pre-ONC201 time point as the baseline image and linearly co-register every subsequent time point to the baseline image space in order to assess voxel-wise change in ADC or CBV. Parametric maps generated will be analyzed alongside post-processed imaging. The anticipated outcomes include the establishment of a robust clinical radiographic dataset and an assessment of the predictive value of nrCBV at baseline and its alteration during ONC201 treatment. Even negative results from this specific analysis in the ONC201 treated population will contribute meaningfully to our understanding of treatment response. This research project represents a significant step towards personalized treatment strategies for H3K27M mutant-DMG patients, aiming to improve outcomes and enhance the quality of life for individuals facing this challenging, fatal diagnosis.
