title: Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor r406 after ocular delivery for retinoblastoma.
abstract: OBJECTIVE
  Retinoblastoma is a childhood cancer of the retina. Clinical trials have shown that local delivery of broad spectrum chemotherapeutic agents is efficacious. Recent studies characterizing the genomic and epigenomic landscape of retinoblastoma identified spleen tyrosine kinase (SYK) as a promising candidate for targeted therapy. The purpose of this study was to conduct preclinical testing of the SYK antagonist R406 to evaluate it as a candidate for retinoblastoma treatment.
  
  
  METHODS
  The efficacy of the SYK antagonist R406 delivered locally in a human orthotopic xenograft mouse model of retinoblastoma was tested. Intraocular exposure of R406 was determined for various routes and formulations.
  
  
  RESULTS
  There was no evidence of efficacy for subconjunctival. R406. Maximal vitreal concentration was 10-fold lower than the minimal concentration required to kill retinoblastoma cells in vitro. Dosage of R406 subconjunctivally from emulsion or suspension formulations, direct intravitreal injection of the soluble prodrug of R406 (R788), and repeated topical administration of R406 all increased vitreal exposure, but failed to reach the exposure required for retinoblastoma cell death in culture.
  
  
  CONCLUSIONS
  Taken together, these data suggest that R406 is not a viable clinical candidate for the treatment of retinoblastoma. This study highlights the importance of pharmacokinetic testing of molecular targeted retinoblastoma therapeutics.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Pritchard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stewart
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: Cori
authors.initials: C
authors.lastname: Bradley
authors.forename: Lyra
authors.initials: L
authors.lastname: Griffiths
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Suryadevara
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.forename: Burgess B
authors.initials: BB
authors.lastname: Freeman
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D005123:Eye / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D010078:Oxazines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019572:Retinal Neoplasms / Q000188:drug therapy*; D012175:Retinoblastoma / Q000188:drug therapy*; D000072377:Syk Kinase
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse