Targeting mutant dicer tumorigenesis in pleuropulmonary blastoma via inhibition of RNA polymerase I

Targeting mutant dicer tumorigenesis in pleuropulmonary blastoma via inhibition of RNA polymerase I

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 deve...

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Published in:Translational research : the journal of laboratory and clinical medicine Vol. 258; pp. 60 - 71
Main Authors: Wong, Megan Rui En, Lim, Kia Hui, Hee, Esther Xuan Yi, Chen, Huiyi, Kuick, Chik Hong, Aw, Sze Jet, Chang, Kenneth Tou En, Syed Sulaiman, Nurfarhanah, Low, Sharon YY, Hartono, Septian, Tran, Anh Nguyen Tuan, Ahamed, Summaiyya Hanum, Lam, Ching Mei Joyce, Soh, Shui Yen, Hannan, Katherine M, Hannan, Ross D, Coupland, Lucy A, Loh, Amos Hong Pheng
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-08-2023
Subjects:
CX-5461
DICER1
patient-derived xenograft model
Pleuropulmonary blastoma
RNA polymerase I
RNase IIIa
RNase IIIb
patient-derived xenograft model
LOF
CC3
PPB
TUNEL
PDX
Pleuropulmonary blastoma
DICER1
RNase IIIa
RNA polymerase I
CX-5461
RNase IIIb
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Summary: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.
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content type line 23
ISSN:1931-5244
1878-1810
DOI:10.1016/j.trsl.2023.03.001