Retinoblastoma Researchers Find Success With Two-drug Combination

Retinoblastoma is a tumor that arises in the cells of the retina, thelight-sensitive tissue at the back of the eyeball, following mutationof the gene RB1. It is the third most common form of cancer in infants.Left untreated, the cancer spreads and is fatal. Retinoblastoma strikesabout 250-350 infants and young children each year in the United States.

The St. Jude study suggests a new approach to treatment that could saveboth lives and vision, according to Michael A. Dyer, PhD, an assistantmember of the department of Developmental Neurobiology. The newtreatment might also prevent recurrence of retinoblastoma in childrenwhose cancer is very advanced, he noted. Dyer is the senior author ofthe Clinical Cancer Care report.

The study showed that combination therapy with topotecan andcarboplatin is superior to the standard triple-drug therapy usingvincristine, carboplatin and etoposide. The new combination eliminatesthe use of etoposide, which is known to increase the risk of thechildren getting a form of leukemia called acute myeloblastic leukemia.The findings also suggest that vincristine, which is used in thestandard combination therapy, contributes little to the treatment ofretinoblastoma, and therefore can be eliminated from therapy.

Dyer's group was prompted to look for new treatments because of thedifficulty in managing this cancer. Patients with retinoblastomausually undergo enucleation (removal of the diseased eye); and childrenwith retinoblastoma in both eyes often must undergo anticancer therapyin order to avoid the loss of both eyes and blindness.

But despite the critical need for new treatments that are moreeffective and have less severe side effects, researchers have beenlimited in their ability to identify new drugs and drug combinationsthat will improve the outcome of retinoblastoma. One reason for thisproblem is that there are not enough patients for researchers to enrollin large clinical trials designed to investigate new treatments, Dyersaid. Therefore, it is critically important that any new treatmentbeing considered for clinical trials have already demonstrated in thelaboratory a high likelihood of success in clinical trials. Until lastyear when researchers at St. Jude developed the first "knockout" modelof retinoblastoma and the two other models presented in this work,there were few options for preclinical studies on retinoblastoma. Aknockout model is one that lacks one or more specific genes; knockoutmodels are developed in order to study specific human diseases causedby gene defects.

The investigators made their findings during a sequence of experiments.First, they tested the ability of drugs and drug combinations to killretinoblastoma tumors removed from patients and grown in tissuecultures. Then the team determined how much drug to use, and how oftento use it, by doing pharmacokinetic studies. Finally, the team testedthe drugs in laboratory models of the cancer they had developed forthis purpose. Pharmacokinetics is the study of the rate of absorption,distribution, breakdown and excretion of drugs from the body.

"Our models of retinoblastoma behave very much like the tumors thatoccur in children, so our investigation of potential new treatments forthis cancer gave us very relevant and useful information, said NikiaLaurie, Ph.D. the paper's first author, who did much of the work onthis project.

The two retinoblastoma models the St. Jude team developed were axenograft model of retinoblastoma, in which a cell line from a tumorremoved from a child grew naturally and was available for testing newdrug combinations; and a genetic model, in which the team injected avirus carrying a gene that induced from one to five individual tumorsin the retina. Importantly, these tumors spread through the bloodvessels of the retina, which is particularly important for futurestudies that could test cancer drugs that work by blocking formation ofblood vessels, according to Dyer.

The St. Jude team plans to use their two new models as a"high-throughput" screen to test many new drugs and drug combinationsrapidly after determining what doses to use based on culture andpharmacokinetic studies. Treatments that appear to be effective willthen be tested in a previously developed "knock-out" laboratory model.This model lacks three critical genes, which causes retinoblastoma."The knock-out model closely mimics the course of the disease inchildren, Dyer said. "So it's the perfect final screening tool toidentify new treatments likely to benefit children in clinical trials."

Dyer previously reported the development of this knock-out model in apaper that appeared in the June 14, 2004, issue of Cell Cycle. Otherauthors of the study include Johnathan K. Gray, Jiakun Zhang, MarkLeggas, Mary Relling and Clinton Stewart (St. Jude); and Merrill Egorin(University of Pittsburgh [PA] Cancer Institute).

This work was supported in part bythe National Eye Institute, National Cancer Institute, Pew CharitableTrust, Research to Prevent Blindness and ALSAC.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized forits pioneering work in finding cures and saving children with cancerand other catastrophic diseases. Founded by late entertainer DannyThomas and based in Memphis, Tenn., St. Jude freely shares itsdiscoveries with scientific and medical communities around the world.No family ever pays for treatments not covered by insurance, andfamilies without insurance are never asked to pay. St. Jude isfinancially supported by ALSAC, its fund-raising organization. For moreinformation, please visit www.stjude.org.