Phase II Study of ASTX727 in Patients with PRC2 loss Malignant Peripheral Nerve Sheath Tumor (MPNST)

项目总结： 恶性周围神经鞘膜瘤(MPNST)，占所有软组织肉瘤(STS)的4%， 代表STS的一种侵袭性亚型，预后较差。MPNST发生在不同的临床环境中：I型 神经纤维瘤病(NF1)相关(45%)，散发性新生(45%)，或放射(RT)相关(10%)。 在分子水平上，MPNSTs共享三种肿瘤抑制基因的高度重复和双等位基因失活 途径：NF1、CDKN2A和多梳抑制复合体2(PRC2)核心成分EED或SUZ12。PRC2 80%以上的高级别MPNST发生丢失，并导致全球H3K27me2/3丢失和异常 发育沉默的主调节因子的转录激活，导致细胞可塑性增强。 MPNST中的PRC2缺失也会导致多个信号通路(如WNT信号)的异常激活，以及 “免疫沙漠”肿瘤微环境，对免疫关卡的阻断具有原发抵抗力。目前， 目前还没有有效的系统疗法为MPNST提供持久的临床益处。 使用专门针对表观遗传调控因子的定制RNAi文库和汇集的负性筛选，我们 确定并确认DNMT1是具有PRC2缺失的头号合成致死候选基因。我们进一步观察到， 与PRC2野生型(Wt)相比，用泛DNMT抑制剂(地他滨)或选择性DNMT1处理 在不同的体内外MPNST模型中，抑制剂(GSK862)的毒性显著增强 PRC2失活。与之前对实体瘤中DNMT抑制剂的研究不同的是，通常证明 最小的抗肿瘤作用，DNMT抑制剂通过以下途径在PRC2-Lost上下文中施加显著的抗肿瘤作用 程序性细胞死亡。我们假设，PrC2的缺失产生了对DNA甲基化的关键依赖- 介导ERV对肿瘤细胞的调节和DNMT的抑制可能是一种新的PRC2治疗策略。 丢失MPNST。 在这里，我们提出了一项概念验证研究人员发起的II期试验来评估ASTX727的疗效 (地西他滨和西达尿苷联合应用)治疗PRC2缺失的MPNSTs患者。二期试验包含了丰富的 治疗前、治疗中和疾病进展时的活组织检查以及探索性相关 在单细胞水平上使用尖端遗传学、表观遗传学和转录组分析的研究，目标是 评估治疗敏感性和耐药性的生物标志物和机制。我们认为这个临床 这项研究将产生关键的生物标记物驱动的临床和翻译信息，用于最终试验 PRC2缺失MPNST中的ASTX727有可能描述其他癌症类型的治疗策略 PRC2基因失活或功能失活。

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.