Retinal Organoid Screening Reveals ABT-737 and Luminespib as Selective Agents Against Tumorigenic Cone Precursors in Retinoblastoma

In this study, we utilized patient RB1⁻/⁻ retinal organoids 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 six candidates exhibiting selective 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 selectively ablated the Rb-like proliferating cone precursors. Ocular pharmacokinetic modeling 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.