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    Bench to Bedside

    Today many organizations use the term “bench to bedside” to describe their programs. But the concept was born 42 years ago in a tiny hospital in Memphis, Tennessee. There, basic scientists and physicians worked in tandem to translate laboratory discoveries into cures. From its humble beginnings, St. Jude Children’s Research Hospital created a worldwide model for bench-to-bedside research.

    Nowhere is that success story more evident than in relation to retinoblastoma, a malignant tumor of the retina. When the late Charles Pratt, MD, began treating children in the early 1960s, cancer research was in its infancy. “The drug options were so limited that I carried my medicines around in an old Seagram’s Crown Royal bag,” said Pratt, a St. Jude physician who pioneered many chemotherapy agents used to treat retinoblastoma and other cancers.

    Today, St. Jude researchers harness technology and knowledge to give clinicians a vast array of treatment options. Michael Dyer, PhD, an assistant member of Developmental Neurobiology, leads a team that is studying normal development of the retina as well as testing new treatments for retinoblastoma. Dyer says the proximity of his lab to the clinic makes research more exciting and relevant to patients.

    “At other institutions, I might do all the same experiments that I do here, but I would just publish my findings and hope that somebody would actually apply what we have found,” says Dyer, who engages in a nearly constant dialogue with Carlos Rodriguez-Galindo, MD, of Hematology-Oncology and Barrett Haik, MD, of the St. Jude Eye Clinic. “Not only are Carlos and Barrett saying, ‘Hey, Mike, have you thought about trying out this drug?’ but I can give them results before they ever get published,” Dyer says. “Things move much quicker here than they would anywhere else.”

    Back to basics

    The retinoblastoma gene was the first tumor suppressor gene cloned in humans, and the mutation that causes the disease involves one culprit, the Rb gene. An individual with an Rb mutation is much more likely to develop retinoblastoma than is a person who does not have the mutation. But the disease’s origins remain an enigma. “You would think that we would know a lot about retinoblastoma,” Dyer says. “But the sad thing is that we know very, very little—in fact, I would say almost nothing—about what happens to make these cells become tumor cells.”

    Dyer and his colleagues have developed new laboratory models to help them track the genetic changes that occur in cells after Rb is mutated. By studying the basic biology of the tumor cells, Dyer hopes to create cancer therapies that target specific pathways or proteins. Such treatments would eliminate the sickness and side effects that accompany general chemotherapy. Many scientists believe that the vast majority of cancers may involve a mutation in the Rb pathway. That’s why many retinoblastoma patients have an increased chance of developing other types of cancer, as well.

    By studying the molecular changes that give rise to retinoblastoma, St. Jude scientists hope to broaden their understanding of normal retinal development and of developmental tumors of the central nervous system.

    Seeking a magic combination

    Although doctors have been treating retinoblastoma for more than a century, no one has yet pinpointed a definitive treatment. The laboratory models created in Dyer’s lab will help St. Jude scientists test chemotherapy drugs for retinoblastoma. To speed the process, the researchers are testing drugs that have already been successfully used to treat other kinds of childhood cancers. Methodically, the scientists try different dosages, various combinations and different lengths of treatment. Then they test whether or not the drug actually travels to the tumor in the eye.

    “Before we began this project, nobody had systematically tried drug after drug in combination to figure out which are the best ways to go,” says Dyer. Many drugs that might work for medulloblastoma or neuroblastoma are perfect candidates for retinoblastoma because these cancers have many similarities.

    St. Jude clinicians help basic scientists factor in the possible side effects of drugs. “There might be a fabulous drug for treating and killing these tumor cells but the child can’t tolerate it,” Dyer says. “So in those cases, it just gets cleared off the slate; we don’t end up wasting our time.”

    When Dyer finds a promising drug combination, an interdisciplinary team considers its inclusion in upcoming treatment plans for St. Jude patients. The new retinoblastoma protocol slated to begin in the summer of 2004 incorporates topotecan and vincristine, two drugs that underwent extensive testing in Dyer’s laboratory. But Dyer is also hoping to continue screening 12 or more drug combinations per year, in a constant search for the ultimate treatment.

    “Before this, Carlos and Barrett would look through the literature and make a best estimate on what might work,” Dyer says. “Now they’re going to have a huge amount of data to base that on, and we’re going to follow the children closely. Do they respond the same way that cells do in culture? We can go from a dish with tumor cells in it to a laboratory model to a patient and back again; I don’t know of anywhere else where that happens in such an efficient way. Without that connection, we would just be doing this blind, and we wouldn’t have that important feedback.

    “St. Jude provides a wonderful sort of environment to do these kinds of things,” Dyer continues. “It’s an amazing place; it really is.”

    Reprinted from Promise magazine, spring 2004

     

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