%0 Journal Article
%T Targeting mutant dicer tumorigenesis in pleuropulmonary blastoma via inhibition of RNA polymerase I.
%A Wong MRE
%A Lim KH
%A Hee EXY
%A Chen H
%A Kuick CH
%A Aw SJ
%A Chang KTE
%A Syed Sulaiman N
%A Low SY
%A Hartono S
%A Tran ANT
%A Ahamed SH
%A Lam CMJ
%A Soh SY
%A Hannan KM
%A Hannan RD
%A Coupland LA
%A Loh AHP
%J Transl Res
%V 258
%N 0
%D 08 2023 14
%M 36921796
%F 10.171
%R 10.1016/j.trsl.2023.03.001
%X 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.