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 sub-pleural 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, 30mg/kg), tumors were smaller and less hemorrhagic than
controls, with significantly decreased cellular proliferation, and increased apoptosis.
As demonstrated in a novel intra-thoracic tumor model of PPB, Pol I inhibition with
CX-5461 could be a tolerable and clinically-feasible therapeutic strategy for mutant
Dicer tumors, inducing anti-tumor effects by decreasing H3K9 methylation and enhancing
p53-mediated apoptosis.
Keywords
Abbreviations:
PPB (Pleuropulmonary blastoma), PDX (patient-derived xenograft), LOF (Loss-of-function), CC3 (Cleaved caspase-3), TUNEL (Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling)To read this article in full you will need to make a payment
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Article info
Publication history
Accepted:
March 7,
2023
Received in revised form:
February 23,
2023
Received:
September 17,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
