Targeting MDM2 and MDMX in retinoblastoma.
Retinoblastoma is the third most common form of cancer in infants, and metastatic retinoblastoma is lethal in approximately 90% of cases. Early detection and aggressive therapy has resulted in a 95% probability of survival for retinoblastoma patients in the United States. However, the United States only represents 3-4% of the retinoblastoma cases worldwide. The majority of children diagnosed with retinoblastoma each year live in developing countries where the probability of survival is closer to 50%. This difference in survival rates reflects poor early detection rates and limited resources for the aggressive therapy necessary to treat retinoblastoma and manage the side effects associated with broad-spectrum systemic chemotherapy in young children. In order to have the most significant impact on retinoblastoma treatment in the United States and worldwide, current efforts have focused on local delivery of targeted chemotherapy. In this review, we summarize recent data showing that the p53 pathway is inactivated in 75% of retinoblastoma patients due to extra copies of the MDM2 and MDMX genes. A small molecule inhibitor of MDM2 called nutlin-3 can induce p53-mediated cell death in retinoblastoma cells. Subconjunctival delivery of nutlin-3 in preclinical models of retinoblastoma confirmed the efficacy of this approach in vivo. The advantage of local application of targeted chemotherapeutic agents such as nutlin-3 is that greater intraocular drug concentrations can be achieved without the side effects associated with systemic broad-spectrum chemotherapy. We propose that subconjunctival administration of targeted chemotherapy may be the best treatment option for children with retinoblastoma in the United States and throughout the developing world because it provides greater tumor response without the costs and complications associated with current treatment protocols.
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Nikia A
NA
Laurie
Chie-Schin
CS
Shih
Chie
C
Schin-Shih
Michael A
MA
Dyer
D018797:Cell Cycle Proteins; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012175:Retinoblastoma / Q000188:drug therapy* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2