Retinoblastoma is the third most common cancer in infants after leukemia and neuroblastoma (nerve cancer). Retinoblastoma that has spread outside the eye is among the deadliest childhood cancers, with an average survival rate of less than 10 percent. Until now, researchers had no reliable animal model in which to test new drugs that might improve the outcome of retinoblastoma in children. However, using this model and two other mouse models developed in the same lab at St. Jude, researchers have already tested effective new drugs and drug combinations that will be used in future retinoblastoma treatments, according to Michael Dyer, Ph.D., assistant member in the St. Jude Department of Developmental Neurobiology. Dyer is senior author of the Cell Cycle report.
The need for new treatments is especially critical for children with bilateral retinoblastoma, cancer in both eyes. Much effort is focused on saving vision in these children by eliminating the cancer using chemotherapy and intensive focal treatments with lasers and cryotherapy, which means killing cancer cells by freezing them. The main goal of these treatments is to save the eyes and, if possible, to avoid or delay radiation therapy. Unfortunately, in many cases, one or both eyes must be removed if other treatments fail. Effective drug therapy would greatly improve both the chance of survival among these children as well as preserve their vision.
A key genetic defect in both children and the St. Jude retinoblastoma mouse is the lack of Rb1, the first tumor suppressor gene identified in humans. The St. Jude model is called a "knockout" because researchers eliminated the gene Rb1, as well as two other cancer-suppressing genes, p107 and p53. A previous attempt made over a decade ago by other researchers to make a retinoblastoma mouse model failed.
"Our knockout mouse model is unique because we knocked out not only Rb1, but also p107 and p53," Dyer said. "The previous knockout model still had p107, which, unlike in humans, compensates for the lack of Rb1. So those mice never developed retinoblastoma."
Another important advantage to the St. Jude retinoblastoma model is that the tumor suppressor genes are only knocked out in the retina of the developing embryo, which is exactly what happens in children with retinoblastoma. As a result of confining the mutation to the developing retina, the mice do not develop other types of cancer and can be bred to pass on the genetic mutations. This allows researchers to breed a large enough population to conduct drug trials.
"Only about 300 children develop retinoblastoma in the United States each year," Dyer said. "It's very difficult to gather enough children in one place to conduct a clinical trial of potential new anti-cancer drugs. But our retinoblastoma model lets us test drugs on many mice in a relatively short time. This advantage has already helped us identify a promising new treatment that physicians are now studying in clinical trials."
The St. Jude knockout mouse model will also be a valuable tool for studying the genetic events that contribute to the onset and progression of retinoblastoma, according to Dyer. "Because the absence of Rb1 is linked to many other cancers, the St. Jude mouse model holds the potential to teach us more about the genetic basis of other cancers as well."
Other authors of the paper are Jiakun Zhang, M.D., Ph.D., and Brett Schweers, Ph.D., both of St. Jude.
This work was supported in part by the National Eye Institute, the National Cancer Institute, the Pew Charitable Trust, Research to Prevent Blindness and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.
Journal
Cell Cycle