A promising therapy to combat brain tumors in children has emerged from a confluence of bold research, scientific insight and luck, a Children’s Mercy research director said Aug. 30 in the latest installment in the UMKC Health Sciences Deans’ Seminar Series.
The research aims to block a pathway that mutant cells often take when forming tumors near the brain stem. The work’s progress and hurdles were detailed by Tom Curran, Ph.D., who is the executive director and chief scientific officer of the Children’s Research Institute and a professor of pediatrics at the UMKC School of Medicine.
His presentation was titled “How mice, sheep, corn lilies and a beer helped children with brain tumors: Targeting the hedgehog pathway in medulloblastoma.”
When he started the hedgehog inhibitor work, Curran already had contributed extensively to the understanding of tumor formation – and knew plenty about mice. He discovered the Fos-Jun tumor-generating complex, and had identified reelin, the gene responsible for reeler, the mutation that makes mice lose muscle control.
Curran wanted to extend his mutation research to the tumors that form during brain development, “so we made the decision that we would take a take a precision medicine approach to medulloblastoma, even though we knew nothing about it at the time.”
He said his team came up with “a very naive concept” for proceeding: to identify molecules involved in tumor formation and then develop inhibitors for them, confirming both the mutations and their inhibition in mouse studies. After cause and prevention were demonstrated in mice, clinical drug trials in humans would follow.
The plan, however naive, has generated significant research success.
“That’s what translational research is about,” he said. “You have to develop a simple model … with milestones that let you know you’re making progress toward the goals.
“The other factor that is really important to this kind of science is luck. You need to be in the right place at the right time.”
The project’s first indication of good timing came quickly.
“Three weeks after we decided we were going to target medulloblastoma, the very first paper came out linking the sonic hedgehog pathway and … these tumors.” (A family of mutant genes with a spiky appearance is called hedgehog genes, and one of those was named after the Sonic Hedgehog computer game a Harvard researcher’s son was fond of.)
Sheep and corn lilies entered the picture when Curran was looking for a hedgehog-path inhibitor to work with and recalled a story about sheep giving birth to one-eyed lambs. What might have been a genetic defect was determined instead to be caused by a chemical in the corn lilies the ewes had eaten. The chemical, named cyclopamine, was found to block the sonic hedgehog path, the effect Curran was looking for. But it also was toxic and eventually seemed unlikely to lead to a suitable drug for humans.
Fortune intervened again when Curran was having a beer with a colleague after a conference in Taos, N.M. The friend was an expert on the sonic hedgehog pathway and referred Curran to another researcher whose team was doing similar work but running out of money for testing. Curran got in touch with the other team and was able to do the testing, which produced good results.
The project also has had its share of challenges to overcome, including recurrence of tumors after initial success in a human trial. That often happens in cancer treatment, Curran said, as drug resistance develops. But a biopsy from that case has provided further information, and trials continue.
Besides his positions at the Children’s Research Institute and UMKC, Curran is the Donald J. Hall Eminent Scholar in Pediatric Research and a professor of cancer biology at the University of Kansas School of Medicine.
Before coming to Kansas City, he led the Translational Brain Tumor Program for a decade at St. Jude Children’s Research Hospital; was deputy scientific director of the Children’s Hospital of Philadelphia Research Institute for another decade; and set up the multi-institution Children’s Brain Tumor Tissue Consortium.
Curran earned his doctorate for studies at the Imperial Cancer Research Fund Laboratories in London. His work has been published in nearly 300 papers and cited more than 50,000 times.