Targeting the p53 pathway in retinoblastoma with subconjunctival nutlin-3a

Rachel C. Brennan, Sara Federico, Cori Bradley, Jiakun Zhang, Jacqueline Flores-Otero, Matthew Wilson, Clinton Stewart, Fangyi Zhu, Kip Guy, Michael A. Dyer

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Retinoblastoma is a rare childhood cancer of the retina that begins in utero and is diagnosed in the first years of life. The goals of retinoblastoma treatment are ocular salvage, vision preservation, and reduction of short- and long-term side effects without risking mortality because of tumor dissemination. To identify better chemotherapeutic combinations for the treatment of retinoblastoma, several groups have developed genetic mouse models and orthotopic xenograft models of human retinoblastoma for preclinical testing. Previous studies have implicated the MDMX protein in the suppression of the p53 pathway in retinoblastoma and shown that the MDM2/MDMX antagonist, Nutlin-3a, can efficiently induce p53-mediated cell death in retinoblastoma cell lines. However, Nutlin-3a cannot be administered systemically to treat retinoblastoma, because it has poor penetration across the blood-ocular barrier. Therefore, we developed an ocular formulation of Nutlin-3a, Nutlin-3aOC, and tested the pharmacokinetics and efficacy of this new formulation in genetic and human retinoblastoma orthotopic xenograft models of retinoblastoma. Here, we show that Nutlin-3aOC specifically and efficiently targets the p53 pathway and that the combination of Nutlin-3aOC with systemic topotecan is a significantly better treatment for retinoblastoma than currently used chemotherapy in human orthotopic xenografts. Our studies provide a new standardized approach to evaluate and prioritize novel agents for incorporation into future clinical trials for retinoblastoma.

Original languageEnglish (US)
Pages (from-to)4205-4213
Number of pages9
JournalCancer Research
Volume71
Issue number12
DOIs
StatePublished - Jun 15 2011

Fingerprint

Retinoblastoma
Heterografts
Retinal Neoplasms
nutlin 3
Proto-Oncogene Proteins c-mdm2
Topotecan
Salvage Therapy
Genetic Models
Medical Genetics
Cell Death
Pharmacokinetics
Clinical Trials
Drug Therapy
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Brennan, R. C., Federico, S., Bradley, C., Zhang, J., Flores-Otero, J., Wilson, M., ... Dyer, M. A. (2011). Targeting the p53 pathway in retinoblastoma with subconjunctival nutlin-3a. Cancer Research, 71(12), 4205-4213. https://doi.org/10.1158/0008-5472.CAN-11-0058

Targeting the p53 pathway in retinoblastoma with subconjunctival nutlin-3a. / Brennan, Rachel C.; Federico, Sara; Bradley, Cori; Zhang, Jiakun; Flores-Otero, Jacqueline; Wilson, Matthew; Stewart, Clinton; Zhu, Fangyi; Guy, Kip; Dyer, Michael A.

In: Cancer Research, Vol. 71, No. 12, 15.06.2011, p. 4205-4213.

Research output: Contribution to journalArticle

Brennan, RC, Federico, S, Bradley, C, Zhang, J, Flores-Otero, J, Wilson, M, Stewart, C, Zhu, F, Guy, K & Dyer, MA 2011, 'Targeting the p53 pathway in retinoblastoma with subconjunctival nutlin-3a', Cancer Research, vol. 71, no. 12, pp. 4205-4213. https://doi.org/10.1158/0008-5472.CAN-11-0058
Brennan RC, Federico S, Bradley C, Zhang J, Flores-Otero J, Wilson M et al. Targeting the p53 pathway in retinoblastoma with subconjunctival nutlin-3a. Cancer Research. 2011 Jun 15;71(12):4205-4213. https://doi.org/10.1158/0008-5472.CAN-11-0058
Brennan, Rachel C. ; Federico, Sara ; Bradley, Cori ; Zhang, Jiakun ; Flores-Otero, Jacqueline ; Wilson, Matthew ; Stewart, Clinton ; Zhu, Fangyi ; Guy, Kip ; Dyer, Michael A. / Targeting the p53 pathway in retinoblastoma with subconjunctival nutlin-3a. In: Cancer Research. 2011 ; Vol. 71, No. 12. pp. 4205-4213.
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