Purpose Retinoblastoma is a childhood cancer of the retina.\nClinical trials have shown that local delivery of broad spectrum\nchemotherapeutic agents is efficacious. Recent studies characterizing\nthe genomic and epigenomic landscape of retinoblastoma\nidentified spleen tyrosine kinase (SYK) as a promising candidate for\ntargeted therapy. The purpose of this study was to conduct\npreclinical testing of the SYK antagonist R406 to evaluate it as a\ncandidate for retinoblastoma treatment.\nMethods The efficacy of the SYK antagonist R406 delivered\nlocally in a human orthotopic xenograft mouse model of retinoblastoma\nwas tested. Intraocular exposure of R406 was determined\nfor various routes and formulations.\nResults There was no evidence of efficacy for subconjunctival.\nR406. Maximal vitreal concentration was 10-fold lower than the\nminimal concentration required to kill retinoblastoma cells in vitro.\nDosage of R406 subconjunctivally from emulsion or suspension\nformulations, direct intravitreal injection of the\nsoluble prodrug of R406 (R788), and repeated topical\nadministration of R406 all increased vitreal exposure, but\nfailed to reach the exposure required for retinoblastoma cell death\nin culture.\nConclusion Taken together, these data suggest that R406 is not a\nviable clinical candidate for the treatment of retinoblastoma. This\nstudy highlights the importance of pharmacokinetic testing of\nmolecular targeted retinoblastoma therapeutics.
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