• Megan Rui En Wong, Kia Hui Lim, Esther Xuan Yi Hee, Huiyi Chen, Chik Hong Kuick, Sze Jet Aw, Kenneth Tou En Chang, Syed SulaimanNurfarhanahNVIVA-KKH Pediatric Brain and Solid Tumor Program, Children's Blood and Cancer Centre, KK Women's and Children's Hospital, Singapore; Department of Neurology, National Neuroscience Institute, Singapore., Sharon Yy Low, Septian Hartono, Anh Nguyen Tuan Tran, Summaiyya Hanum Ahamed, Ching Mei Joyce Lam, Shui Yen Soh, Katherine M Hannan, Ross D Hannan, Lucy A Coupland, and LohAmos Hong PhengAHPVIVA-KKH Pediatric Brain and Solid Tumor Program, Children's Blood and Cancer Centre, KK Women's and Children's Hospital, Singapore; Duke-NUS School of Medicine, Singapore; Department of Pediatric Surgery, KK Women's and Children's Ho.
• VIVA-KKH Pediatric Brain and Solid Tumor Program, Children's Blood and Cancer Centre, KK Women's and Children's Hospital, Singapore.
• Transl Res. 2023 Aug 1; 258: 607160-71.

AbstractDICER1 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.Copyright © 2023 Elsevier Inc. All rights reserved.

23 keywords...

hide…