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

ASTX727 在 PRC2 缺失恶性周围神经鞘瘤 (MPNST) 患者中的 II 期研究

• 批准号: 10707164
• 负责人: Ping Chi
• 金额: $ 57.55万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707164
• 关键词: Phase; II; Study; ASTX727; Patients

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.

项目概要： 恶性周围神经鞘瘤（MPNST）占所有软组织肉瘤（STS）的4%， 代表预后不良的侵袭性STS亚型。MPNST发生在不同的临床环境中：I型 神经纤维瘤病（NF 1）相关（45%）、散发性新发（45%）或放射（RT）相关（10%）。 在分子水平上，MPNST共享三种肿瘤抑制基因的高度复发性和双等位基因遗传失活。 途径：NF 1、CDKN 2A和Polycomb抑制复合物2（PRC 2）核心组分、EED或SUZ 12。PRC2 超过80%的高级MPNST发生丢失，并导致H3 K27 me 2/3的全局丢失和异常丢失。 转录激活发育沉默的主调节因子，导致增强的细胞可塑性。 MPNST中的PRC 2缺失还导致多种信号传导途径（例如WNT信号传导）的异常激活， “免疫沙漠”肿瘤微环境和对免疫检查点阻断的原发性抗性。目前， 没有为MPNST提供持久临床益处的有效全身疗法。 使用专门针对表观遗传调节因子的定制RNAi文库和合并的阴性筛选， 鉴定并验证DNMT 1为具有PRC 2损失的最高合成致死候选物。我们进一步观察到， 与PRC 2-野生型（wt）相比，用泛DNMT抑制剂（地西他滨）或选择性DNMT 1抑制剂（地西他滨）治疗 抑制剂（GSK 862）在各种体外和体内MPNST模型中导致显著增强的毒性， PRC 2失活。与先前的DNMT抑制剂在实体瘤中的研究相反， 最小的抗肿瘤作用，DNMT抑制剂在PRC 2缺失背景下通过以下途径产生显著的抗肿瘤作用： 程序性细胞死亡我们假设PRC 2的缺失对DNA甲基化产生了关键的依赖性- 介导的ERV调节肿瘤细胞和DNMT抑制可能代表一种新的治疗策略，在PRC 2- 损失MPNST。 在这里，我们提出了一个概念验证启动的II期试验，以评估ASTX 727的疗效 （地西他滨和西氮尿苷的组合）在PRC 2缺失MPNST患者中的应用。第二阶段试验富含 治疗前、治疗中和疾病进展时的研究活检，以及探索性相关 在单细胞水平上使用尖端的遗传、表观遗传和转录组分析进行研究，目标是 评估生物标志物和治疗敏感性和耐药性的机制。我们认为，这种临床 研究将产生关键的生物标志物驱动的临床和翻译信息，用于 PRC 2缺失MPNST中的ASTX 727有可能描述其他癌症类型的治疗策略， PRC 2的遗传或功能失活。