DDDR-42. Modeling and Translating Precision Therapies for NF1-Associated Tumors Across the Disease Spectrum

Abstract Patients with Neurofibromatosis Type 1 (NF1) are predisposed to central and peripheral nervous system tumors, notably malignant peripheral nerve sheath tumors (MPNSTs) and gliomas. In NF1, MPNSTs arise through a stepwise progression: NF1 loss in Schwann cells (SCs) initiates plexiform neurofibromas (PN), which can evolve into atypical neurofibromas (ANF), usually marked by CDKN2A/B deletions. Loss of PRC2 function, usually by loss of SUZ12, is a key driver of ~80% of MPNSTs, profoundly altering gene regulation. To model this progression, we used CRISPR editing in immortalized human SCs, iPSC-derived SCs, and primary mouse SCs from Nf1-/- sciatic nerve. These systems enabled preclinical drug testing and clinical translation. We developed an immunocompetent mouse ANF model via Nf1 and Cdkn2a/b deletion in primary Schwann cells. This model revealed Cdkn2a/b loss enhances immune evasion, alters the tumor metabolome, and confers sensitivity to Mdm2 and folate biosynthesis inhibitors in vitro and in vivo, which synergize with MEK inhibition. Synthetic drug sensitivity screens in NF1- and SUZ12-deficient human SCs revealed new candidates enhancing the effects of MEK inhibition in NF1-deficient SCs in vitro and in vivo and showed PRC2 loss sensitizes SCs to HDAC, AURK, and some DNMT inhibitors. Combining MEK and HDAC inhibitors (e.g., mirdametinib + vorinostat) led to durable tumor regression in vivo and supported our initiation of an early phase window of opportunity trial now open (NCT06693284). Two of our patient cases illustrate clinical potential: one with refractory, H3K27me3-negative MPNST had pain relief and reduced PET activity on selumetinib + vorinostat and remained alive more than two years after failure of all other therapies; another, an 11-year-old with NF1 and H3K27M-mutant spinal glioma, remained recurrence-free for over two years on the same combination. These integrated efforts advance several translational platforms to develop and implement targeted therapies across the NF1 tumor spectrum.