Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor R406 after ocular delivery for retinoblastoma

Eleanor M. Pritchard; Elizabeth Stewart; Fangyi Zhu; Cori Bradley; Lyra Griffiths; Lei Yang; Praveen Kumar Suryadevara; Jiakun Zhang; Burgess B. Freeman; R. Kiplin Guy; Michael A. Dyer

doi:10.1007/s11095-014-1399-y

Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor R406 after ocular delivery for retinoblastoma

Eleanor M. Pritchard, Elizabeth Stewart, Fangyi Zhu, Cori Bradley, Lyra Griffiths, Lei Yang, Praveen Kumar Suryadevara, Jiakun Zhang, Burgess B. Freeman, R. Kiplin Guy, Michael A. Dyer

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Purpose: 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.

Conclusion: 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.

Original language	English
Pages (from-to)	3060-3072
Number of pages	13
Journal	Pharmaceutical Research
Volume	31
Issue number	11
DOIs	https://doi.org/10.1007/s11095-014-1399-y
State	Published - Nov 2014

Bibliographical note

Funding Information:
The authors thank Justin Thurman and Alex Su for help collecting tissue samples. The authors thank Justina McEvoy, Claudia Benavente and Daniel Hiler for providing murine vitreous. The authors thank William Wu and Jianrong Wu in the SJCRH Department of Biostatistics. The authors thank William Caufield for preliminary bioanalytical assay development. We thank the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital for funding. Eleanor Pritchard was funded by an SJCRH Academic Programs special fellowship. This work was also supported by a grant from the National Cancer Institute [R01CA168875-01] and by the Howard Hughes Medical Institute.

Publisher Copyright:
© 2014 The Author(s).

Keywords

Ocular drug delivery
R406
Retinoblastoma
Spleen tyrosine kinase

ASJC Scopus subject areas

Biotechnology
Molecular Medicine
Pharmacology
Pharmaceutical Science
Organic Chemistry
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s11095-014-1399-y

Cite this

@article{583ba03808484a938339b0a7f4915737,

title = "Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor R406 after ocular delivery for retinoblastoma",

abstract = "Purpose: 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.Conclusion: 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.",

keywords = "Ocular drug delivery, R406, Retinoblastoma, Spleen tyrosine kinase",

author = "Pritchard, {Eleanor M.} and Elizabeth Stewart and Fangyi Zhu and Cori Bradley and Lyra Griffiths and Lei Yang and Suryadevara, {Praveen Kumar} and Jiakun Zhang and Freeman, {Burgess B.} and Guy, {R. Kiplin} and Dyer, {Michael A.}",

note = "Funding Information: The authors thank Justin Thurman and Alex Su for help collecting tissue samples. The authors thank Justina McEvoy, Claudia Benavente and Daniel Hiler for providing murine vitreous. The authors thank William Wu and Jianrong Wu in the SJCRH Department of Biostatistics. The authors thank William Caufield for preliminary bioanalytical assay development. We thank the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children{\textquoteright}s Research Hospital for funding. Eleanor Pritchard was funded by an SJCRH Academic Programs special fellowship. This work was also supported by a grant from the National Cancer Institute [R01CA168875-01] and by the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2014 The Author(s).",

year = "2014",

month = nov,

doi = "10.1007/s11095-014-1399-y",

language = "English",

volume = "31",

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T1 - Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor R406 after ocular delivery for retinoblastoma

AU - Pritchard, Eleanor M.

AU - Stewart, Elizabeth

AU - Zhu, Fangyi

AU - Bradley, Cori

AU - Griffiths, Lyra

AU - Yang, Lei

AU - Suryadevara, Praveen Kumar

AU - Zhang, Jiakun

AU - Freeman, Burgess B.

AU - Guy, R. Kiplin

AU - Dyer, Michael A.

N1 - Funding Information: The authors thank Justin Thurman and Alex Su for help collecting tissue samples. The authors thank Justina McEvoy, Claudia Benavente and Daniel Hiler for providing murine vitreous. The authors thank William Wu and Jianrong Wu in the SJCRH Department of Biostatistics. The authors thank William Caufield for preliminary bioanalytical assay development. We thank the American Lebanese Syrian Associated Charities (ALSAC) and St Jude Children’s Research Hospital for funding. Eleanor Pritchard was funded by an SJCRH Academic Programs special fellowship. This work was also supported by a grant from the National Cancer Institute [R01CA168875-01] and by the Howard Hughes Medical Institute. Publisher Copyright: © 2014 The Author(s).

PY - 2014/11

Y1 - 2014/11

N2 - Purpose: 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.Conclusion: 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.

AB - Purpose: 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.Conclusion: 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.

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KW - R406

KW - Retinoblastoma

KW - Spleen tyrosine kinase

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Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor R406 after ocular delivery for retinoblastoma

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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