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Lookup NU author(s): Dr Joe Kelk, Dr Agata Rozanska, Eleni Sotiriadou, Dan AstleyORCiD, Raf Hussain, Adrienne Unsworth, Dr Rachel QueenORCiD, Dr Jonathan Coxhead, Professor David SteelORCiD, Professor Lyle ArmstrongORCiD, Dr Ian HardcastleORCiD, Professor Gareth VealORCiD, Professor Majlinda LakoORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Retinoblastoma (Rb) features proliferating cone precursors, particularly those in the G2/M phase, as a major driver population revealed by recent single-cell transcriptomic studies, though other molecular subtypes with distinct cellular origins also contribute to tumor heterogeneity. In the current study, we utilized patient RB1⁻/⁻ retinal organoids, which model a cone-precursor derived subtype of Rb, to evaluate the cytotoxic efficacy and selectivity of candidate therapeutics targeting these tumor-initiating cells. A primary screen of 37 compounds identified 11 with significant cytotoxicity, which was subsequently refined to 6 candidates exhibiting activity against proliferating cone precursors. Among these, ABT-737 and luminespib emerged as lead compounds, demonstrating dose-dependent depletion of Ki-67⁺/RXRγ⁺ cone cells and strong apoptotic induction, evidenced by Caspase-3 activation and Annexin V/7-AAD flow cytometry, without inducing necrosis. Single-cell RNA sequencing confirmed that both agents targeted the Rb-like proliferating cone precursors. Ocular pharmacokinetic modelling using pluripotent stem cell-derived RPE monolayers revealed limited permeability across the outer blood-retinal barrier for both drugs; however, luminespib showed moderate translocation, likely due to its lower molecular weight. In contrast, the uptake of ABT-737 by the retinal organoids was more efficient than that of luminespib. Together, these findings highlight ABT-737 and luminespib as potential therapeutic candidates against a cone-precursor subtype of Rb and demonstrate the utility of integrated retinal organoid and RPE models for preclinical drug screening and pharmacokinetic evaluation. However, validation in additional retinoblastoma subtypes beyond cone precursor-derived tumors is essential to determine broader therapeutic applicability and efficacy. Future studies should prioritize testing these agents across diverse Rb genomic and phenotypic subtypes to address potential heterogeneity in treatment response.
Author(s): Kelk J, Rozanska A, Sotiriadou E, Astley D, Hussain R, Unsworth A, Gangar A, Robinson A, Queen R, Coxhead J, Steel DH, Armstrong L, Parulekar M, Hardcastle I, Veal GJ, Lako M
Publication type: Article
Publication status: Published
Journal: Molecular Therapy - Oncology
Year: 2026
Volume: 34
Issue: 1
Print publication date: 19/03/2026
Online publication date: 19/02/2026
Acceptance date: 16/02/2026
Date deposited: 06/03/2026
ISSN (electronic): 2950-3299
Publisher: Cell Press
URL: https://doi.org/10.1016/j.omton.2026.201160
DOI: 10.1016/j.omton.2026.201160
Data Access Statement: The scRNA-seq data are submitted to the Gene Expression Omnibus under the accession number GSE305503.
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