ID #494 Defining the role of PDGFRa signaling in sonic hedgehog medulloblastoma leptomeningeal metastases

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. It has a high five-year survival rate of ∼70-80%. However, most patients typically receive craniospinal irradiation and systemic chemotherapy to prevent leptomeningeal metastases (LM). Despite this aggressive treatment regimen, LM still occurs in most patients at tumor recurrence. This makes LM a major treatment challenge within the neuro-oncology field and highlights a critical need to understand the underlying mechanisms of MB LM. To date, only a few genes have been identified as associated with MB LM. One of the most relevant is the platelet-derived growth factor receptor alpha (PDGFRa) signaling pathway. However, limited functional studies have been conducted in vivo to verify the extent that PDGFRa signaling contributes to MB LM. This project aims to understand the role PDGFRa signaling plays in SHH MB LM by using a highly relevant sporadic SHH MB GEM model with high LM incidence and a novel CNS drug delivery platform. My central hypothesis is that targeting PDGFRa signaling will control the expansion of MB LM and extend survival time. This project leverages a novel SHH MB GEM model, Ptch1-CKO (Ptf1acre/+; Ptch1fl/fl; Atoh1GFP), where mutagenesis occurs in 1000 cerebellar granule neuron precursors. Most importantly, this Ptch1-CKO GEM model is highly penetrant (77/91 mice, 85%), has short tumor latency (mean ∼13.9 weeks), frequent brain LM (46/50 mice, 92%), and spinal cord LM (5/50 mice, 10%). We are generating Ptch1-CKO GEM with either PDGFRa null or constitutively active alleles to assess effects on LM incidence and location. In addition, we have nanoformulated Avapritinib, a highly selective PDGFRa specific tyrosine kinase inhibitor, with fucoidan to pharmacologically inhibit PDGFRa signaling including at LM sites. This work will provide better insight into the metastatic role of PDGFRa in MB LM with the goal to improve therapeutic interventions for medulloblastoma.