During an introductory tour shortly after he joined St. Jude, he met children being treated for retinoblastoma. He asked their doctors how the 15,000-plus research publications on the RB1 pathway had led to progress in treating the cancer.

“I expected them to tell me a great story of success—and they said it’s had absolutely no impact whatsoever,” he recalls. Dyer, a basic scientist, suddenly realized that in all of his years of training at Harvard University and Harvard Medical School, he had never met with a patient, a patient’s family, or even a treating physician. He had no concept of what constituted clinical research. There was a “complete disconnect” between his bench and the patient bedside, he says—a gap he feels is common at academic research centers despite all the chatter about translational research.

In response, Dyer pulled together a team of clinicians, pharmacologists, and medicinal chemists, among others, to explore the basic biology of retinoblastoma and use those insights to devise effective treatments.

The team took a comprehensive, unbiased look at the disease, including molecular, cellular, and chemical analyses of tumor cells. Dyer and his colleagues engineered one of the first knockout mouse models of the cancer as well as the first orthotopic xenograft. When a tumor has to be removed from a patient’s eye, Dyer can take a small piece of the tumor and implant it in a mouse eye, where it retains the characteristics of the human tumor.

To help speed new treatments, St. Jude established its own drug development facility. Pharmaceutical companies have little interest in developing agents that will be used by relatively few patients, Dyer says. “These are essentially orphan drugs.”

Historically, researchers have focused on the genetic component of retinoblastoma. Because the disease progresses so quickly—a change in the RB1 gene very quickly progresses to cancer—the assumption was that as soon as the RB1 gene is mutated, there must be many other mutations (genomic instability) that quickly move the cells through the many steps toward cancer development.

“But the opposite is true,” Dyer says. Based on whole genome sequencing, he says, they found that “Retinoblastoma has fewer genetic mutations of any other cancer we analyzed. So it’s not just genetically driven.”

In contrast, when the Rb mutation occurs, epigenetic changes lead to a mix-up in normal developmental programs. The team found that genes in multiple developmental pathways that should have been silent were functioning. Retinal cells began expressing genes found in other cell types, including SYK. Outside of its normal function, SYK also has been found to be an important cancer driver in some leukemias.

Dyer and colleagues are working on a formula of the Syk inhibitor, R406, that can be delivered to the eye. They plan to test it first in his mouse model of retinoblastoma and then, if successful, move into Phase I studies with patients.

“We can now say in a very accurate way that the epigenetic changes we see are required for tumor growth,” he says. “And we can target those changes with drugs.”

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