Phase II Study of ASTX727 in Patients with PRC2 loss Malignant Peripheral Nerve Sheath Tumor (MPNST) - Project Summary: Malignant peripheral nerve sheath tumor (MPNST), accounting for 4% of all soft tissue sarcomas (STS), represents an aggressive subtype of STS with poor prognosis. MPNSTs occur in distinct clinical settings: type I neurofibromatosis (NF1)-associated (45%), sporadic de novo (45%), or radiation (RT)-associated (10%). Molecularly, MPNSTs share highly recurrent and biallelic genetic inactivation of three tumor suppressor pathways: NF1, CDKN2A, and Polycomb repressive complex 2 (PRC2) core components, EED or SUZ12. PRC2 loss occurs in more than 80% of all high-grade MPNSTs, and results in global loss of H3K27me2/3 and aberrant transcriptional activation of developmentally silenced master regulators, leading to enhanced cellular plasticity. PRC2 loss in MPNST also leads to aberrant activation of multiple signaling pathways (e.g. WNT signaling), an “immune desert” tumor microenvironment, and primary resistance to immune checkpoint blockade. Currently, there are no effective systemic therapies that provide durable clinical benefit for MPNST. Using a custom RNAi library specifically targeting epigenetic regulators and a pooled negative screen, we identified and validated DNMT1 as the top synthetic lethal candidate with PRC2 loss. We further observed that compared to PRC2-wild-type (wt), treatment with a pan-DNMT inhibitor (decitabine) or a selective DNMT1 inhibitor (GSK862) resulted in significantly enhanced toxicity in various in vitro and in vivo MPNST models with PRC2 inactivation. In contrast to previous studies of DNMT inhibitors in solid tumors that typically demonstrated minimal antitumor effects, DNMT inhibitors imposed significant antitumor effect in the PRC2-loss context through programmed cell death. We hypothesize that PRC2 loss creates a critical dependence on the DNA methylation- mediated ERV regulation in tumor cells and DNMT inhibition may represent a novel therapeutic strategy in PRC2- loss MPNSTs. Here, we propose a proof-of-concept investigator-initiated phase II trial to evaluate the efficacy of ASTX727 (combination of decitabine and cedazuridine) in patients with PRC2-loss MPNSTs. The phase II trial is rich in pre-treatment, on-treatment, and at disease progression research biopsies, as well as exploratory correlative studies using cutting-edge genetic, epigenetic, and transcriptome analyses at single cell level with the goals to evaluate for biomarkers and mechanisms of therapeutic sensitivity and resistance. We believe that this clinical study will generate the pivotal biomarker-driven clinical and translational information for a definitive trial of ASTX727 in PRC2-loss MPNST with the potential to delineate therapeutic strategies in other cancer types with genetic or functional inactivation of PRC2.
