Multimodal Systems for Molecular Profiling and Therapeutic Tracking of DIPG

Pediatric diffuse intrinsic pontine gliomas (DIPG) and diffuse midline glioma (DMG) are devastating childhood brain tumors, with few patients surviving greater than 2 years. The current gold standard to monitor a tumor’s response to therapy is by outlining the tumor margin via radiographic imaging (MRI). If a tumor is found to progress, clinicians can pivot to a new therapy designed for a recurrent DIPG/DMG. Unfortunately, MRI scans can be technically difficult to interpret and radiation or other treatment-induced inflammation can masquerade as tumor growth (known as “pseudo-progression”), further complicating interpretation and delaying proper treatment. Recent work in our lab and others has discovered that circulating tumor DNA (cf-tDNA) in cerebrospinal fluid (CSF) and plasma, that can be quantified using droplet digital polymerase chain reaction (ddPCR), can offer key information that supplements and often precedes a tumor’s response to treatment on MRI. We have developed the feasibility of multiple other novel biomarkers that may offer improved monitoring sensitivity, precision, or alternative signals that provide important and complementary information to clinicians. The objective of this proposal is to design and test assays for alternative disease biomarkers, specifically tumor associated proteins (i.e. H3K27M and TP53) and associated epigenetic marks (Aim 1), mutant mitochondrial DNA (Aim 2), and multiple patient-specific DNA mutations identified via biopsy sequencing (Aim 3). Finally, we will assess the impact of our integrated multi-modal data approach on disease measurement and test various machine-learning algorithms for classification of samples (Aim 4). By uncovering the unique kinetics of each of these novel correlate signals and offering them to DIPG/DMG patients, we will enable an unprecedented level of information to help supplement radiographic imaging and properly inform patient care.