Functional Engagement and Effect of RAF-targeted Therapies in Glioma

Award: $180,000 over 2 years (2020-2022)
Principal Investigators: Dr. Karisa Schreck, Assistant Professor of Neurology, Johns Hopkins University-School of Medicine

An accurate understanding of drug penetration, target inhibition in the brain, and prognostic biomarkers is lacking in PLGA. This is due in part to the limitations of obtaining serial biopsies from patients with brain tumors. Detailed genomic characterization over the past decade has revealed that, while PLGA is a distinct entity, it shares some molecular drivers with pediatric HGG (pHGG) and adult HGG (aHGG). A common driver in PLGA is dysregulation of the RAS signaling pathway via activating BRAF-fusions or point mutations in p.V600E. Implementation of RAF and MEK inhibitors (RAFi/MEKi) against these oncogenes has had some successes in PLGA, but very little is known about blood-brain barrier penetration, target inhibition in the brain, combination with other modalities, and optimal duration of therapy. Moreover, effective biomarkers of response are lacking, making clinical trials challenging to conduct given the long natural history of this disease and lack of prognostic intermediaries. propose to determine RAFi/MEKi penetration and target engagement in non-enhancing and enhancing brain tumor tissue as a surrogate for penetration into PLGA. Through the ongoing clinical trials run by our multi-institutional team, we are acquiring pre-/post- RAFi/MEKi brain tumor specimens in order to answer critical questions for PLGA drug delivery and treatment. We will determine intra-tumoral drug concentrations, functional ERK inhibition, and correlation with response to treatment. We will also identify a kinome signature for treatment sensitivity or resistance using pre-/post- treatment specimens and serial blood samples.