Abstract
Purpose :
To reveal targetability of polo-like kinase 1 (PLK1) with a small molecular inhibitor ON-01910.Na using retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model.
Methods :
Transcriptomic analysis on patient retinoblastoma tissues was done to find key pathway and to select key factor of retinoblastoma. Subsequently, antitumor activity of ON-01910.Na, the drug targetting the selected key factor, was investigated in both cellular and animal levels.
Results :
Transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1 pathway was upregulated. In the investigation of antitumor activity of ON-01910.Na, a PLK1 inhibitor, it was found that cytotoxicity induced by ON-01910.Na was tumor specific and dose dependent in retinoblastoma cells, while nontumor cells were minimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug penetrability with multilayer cell death. Posttreatment transcriptomic findings revealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition and eventually resulted in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantly reduced with ON-01910.Na treatments.
Conclusions :
Local treatment of ON-01910.Na may be a novel, effective modality benefiting patients with PLK1-aberrant retinoblastoma.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.