iPSC Model Uncovers Olaparib-Selumetinib Combination Suppresses Malignant Peripheral Nerve Sheath Tumor Growth

The progression of benign plexiform neurofibromas (PNFs) to deadly malignant peripheral nerve sheath tumors (MPNSTs) is a critical challenge in Neurofibromatosis Type 1 (NF1). This transformation is poorly understood but is commonly linked to sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Current treatments for MPNSTs are often ineffective, highlighting an urgent need for better models to dissect disease mechanisms and identify novel therapeutic targets, particularly for advanced or recurrent disease.

Researchers developed an iPSC-derived neural crest (NC) model to mimic MPNST progression through gene editing. They created NF1-CDKN2A double-knockout (2KO) NCs and NF1-CDKN2A-PRC2 triple-knockout (3KO) NCs. These cells were used to form neurofibroma-like tumors in vivo and to generate 3D NC spheroid models for high-throughput screening of epigenetic compounds. The most promising drug candidates, including Olaparib-Selumetinib combination, were then tested in a human MPNST PDX mouse model to assess their impact on tumor growth.

The 2KO NCs formed neurofibroma-like tumors in vivo, demonstrating the requirement for p14ARF and p16INK4a inactivation. Crucially, additional PRC2 loss in 3KO NCs disrupted pluripotency and induced mesenchymal stem cell-like features. This 3KO state led to global chromatin reorganization, preventing gliogenesis by SOX10 silencing and activating neuro-mesenchymal transcriptional programs that recapitulate the PNF-ANNUBP-MPNST progression. Upon nerve engraftment, 3KO NC spheres formed MPNST-like tumors in vivo, mimicking an early-stage MPNST. High-throughput screening of epigenetic compounds in 3D NC spheroids revealed that Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibited selective efficacy in PRC2-deficient spheroids.

The Olaparib-Selumetinib combination was well tolerated and significantly suppressed tumor growth in a human MPNST PDX mouse model.