Abstract：
DICER1 mutations predispose to increased risk for various cancers, particularly pleuropulmonary blastoma (PPB), the commonest lung malignancy of childhood. There is a paucity of directly actionable molecular targets as these tumors are driven by loss-of-function mutations of DICER1. Therapeutic development for PPB is further limited by a lack of biologically and physiologically-representative disease models. Given recent evidence of Dicer\'s role as a haploinsufficient tumor suppressor regulating RNA polymerase I (Pol I), Pol I inhibition could abrogate mutant Dicer-mediated accumulation of stalled polymerases to trigger apoptosis. Hence, we developed a novel subpleural orthotopic PPB patient-derived xenograft (PDX) model that retained both RNase IIIa and IIIb hotspot mutations and recapitulated the cardiorespiratory physiology of intra-thoracic disease, and with it evaluated the tolerability and efficacy of first-in-class Pol I inhibitor CX-5461. In PDX tumors, CX-5461 significantly reduced H3K9 di-methylation and increased nuclear p53 expression, within 24 hours\' exposure. Following treatment at the maximum tolerated dosing regimen (12 doses, 30 mg/kg), tumors were smaller and less hemorrhagic than controls, with significantly decreased cellular proliferation, and increased apoptosis. As demonstrated in a novel intrathoracic tumor model of PPB, Pol I inhibition with CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant Dicer tumors, inducing antitumor effects by decreasing H3K9 methylation and enhancing p53-mediated apoptosis.
摘要：
DICER1突变易患各种癌症的风险增加，特别是胸膜肺母细胞瘤（PPB），儿童时期最常见的肺部恶性肿瘤。由于这些肿瘤是由DICER1的功能丧失突变驱动的，因此缺乏可直接操作的分子靶标。PPB的治疗发展进一步受到缺乏生物学和生理学代表性疾病模型的限制。鉴于最近的证据表明Dicer作为单倍体不足的肿瘤抑制因子调节RNA聚合酶I（PolI）的作用，PolI抑制可以消除突变Dicer介导的停滞聚合酶积累以触发细胞凋亡。因此，我们开发了一种新的胸膜下原位PPB患者来源的异种移植（PDX）模型，该模型保留了RNaseIIIa和IIIb热点突变，并概述了胸内疾病的心肺生理。并评估了一级PolI抑制剂CX-5461的耐受性和疗效。在PDX肿瘤中，CX-5461显著降低H3K9双甲基化，增加细胞核p53表达，在24小时内暴露。在最大耐受给药方案治疗后（12剂，30mg/kg），肿瘤比对照组小，出血少，细胞增殖显著减少，和增加细胞凋亡。正如在新的PPB胸内肿瘤模型中所证明的那样，用CX-5461抑制PolI可能是突变Dicer肿瘤的一种可耐受且临床可行的治疗策略，通过降低H3K9甲基化和增强p53介导的细胞凋亡来诱导抗肿瘤作用。
