Taylor's team theorizes that a cluster of stem and progenitor cells in the developing cerebellum could be identified and treated before medulloblastoma can develop.Credit: LIVING ART ENTERPRISES / SCIENCE PHOTO LIBRARY
In the late 1960s, paediatric neuropathologist Lucy Rorke started to study a small group of undifferentiated cells in the tenth lobe of the cerebellar vermis in children. She believed these cells were the origin of medulloblastoma, the most common malignant brain tumour in children.
“These cells were not accepted as the likely cellular origin for medulloblastoma by other investigators in the field at the time,” says neurosurgeon Michael Taylor, director of the Pediatric Neuro-Oncology Research Program at Texas Children’s Hospital and Baylor College of Medicine. But scientists now know that Rorke was right, and Taylor hopes to use that knowledge to prevent medulloblastoma before it has a chance to develop. “I’m tired of trying to cure cancer,” Taylor says. Instead, he wants to prevent it.
Current treatments for brain tumours often fail, and the side effects can be debilitating. Some tumours require a complex surgery, followed by radiation therapy to the entire developing brain and spinal cord. “If your brain is trying to grow and remodel to become an adult brain, that just doesn’t happen after these treatments,” Taylor says. Many children treated for brain tumours experience cognitive disabilities, neuroendocrine disorders that may require hormone replacement therapy, and other health problems resulting from radiation therapy. In addition to reducing quality of life, these side effects can jeopardize cancer survivors’ ability to live independently as adults.
“My vision is that no family ever has to face this devastating diagnosis or the aggressive therapies we use to treat it,” says Taylor. Prevention is particularly important given that brain cancers are the most common solid tumour in children. “This is because a kid’s brain grows faster than the rest of the body,” Taylor explains. “A two-year-old has an adult-sized head.” This fast rate of cell division creates room for subtle errors, increasing the chance that a cancer-causing mutation may arise.
“Despite being the most common childhood cancer, kids diagnosed with medulloblastoma are still dying, and those who survive may be terribly hurt by the treatment,” Taylor says. Prevention, then, is preferable to a cure, and by building on the knowledge Rorke discovered more than half a century ago, Taylor and his team at Texas Children’s Hospital are advancing towards that goal.
Exploring an oncogene
As Taylor’s team worked to improve the management of the cancer, they explored the genetics behind the most common type, known as group four medulloblastoma (Hendrikse, L.D. et al. Nature 609, 1021–1028; 2022). “Medulloblastoma cells are stuck in a perpetually primitive state,” says Tamra Ogilvie, professor of paediatric haematology-oncology at Baylor College of Medicine and co-author of the study. “We wanted to characterize the effect of a really important oncogene called OTX2.”
OTX2, Ogilvie says, “puts the brakes on differentiation, the ability of these medulloblastoma cells to proceed through normal development.” Within a region of the developing cerebellum called the rhombic lip, expression of OTX2 helps to maintain a cluster of stem and progenitor cells — the same cells that Rorke studied decades ago. “It fuels medulloblastoma growth,” says Ogilvie.
These undifferentiated cells in the rhombic lip represent a promising treatment target. Ogilvie, Taylor and their colleagues showed that preventing the expression of OTX2 takes the developmental brakes off these cells, enabling them to differentiate normally into harmless neurons. Their team hopes one day to use this approach to prevent the development of medulloblastoma and avoid the need for surgery or radiation therapy altogether.
Steps to a targeted therapy
In 2023, Taylor and Ogilvie both relocated from Canada to Texas Children’s Hospital in Houston — the perfect place to move the research from the laboratory to clinical care.
Taylor is now a member of the largest paediatric neurosurgery team in the United States at Texas Children’s, which is consistently ranked among the top children’s hospitals in the country. The 10 full-time paediatric neurosurgery faculty members at Texas Children’s perform 1300 major neurosurgical cases per year, spanning the range of paediatric neurologic conditions, and the hospital boasts one of the United States’ busiest paediatric brain and spinal tumour surgical programmes. “Throughout my career, I’ve been inspired by the cancer research taking place at Texas Children’s,” Taylor said when he came onboard in early 2023. “I am honoured to be joining this collaborative, cutting-edge team.”
In his new position, Taylor hopes to develop an affordable and non-invasive test that could be administered in the year after birth to detect medulloblastoma. Early detection of this cancer, which tends to arise during fetal development between the end of the first trimester and the beginning of the second trimester, could open a new treatment window.
Drawing a comparison between cells that trigger medulloblastoma and the polyps that can signal colon cancer, Taylor’s team has now located what he calls the ‘cerebellar polyp’ — the cluster of stem and progenitor cells that could be identified and treated before a child develops full-fledged medulloblastoma.
This cerebellar polyp might be even more useful than a colon cancer polyp, which can crop up almost anywhere in the colon, because as Taylor explains, “the cerebellar polyp always occurs in exactly the same spot.”
The team is therefore searching for a biomarker that could be used to diagnose and then target medulloblastoma at this early stage. “We’re trying to identify a specific cellular fingerprint,” Ogilvie explains. “We need to look for biomarkers that differentiate the stem and progenitor cells from all of the other cells in the tumour.”
“Fetal stem cells have proteins on their surfaces that are not found on any other cells and are not present after birth,” says Taylor. Those proteins could serve as highly specific therapeutic targets.
Taylor knows that making big ideas a reality takes teamwork, and he plans to expand that tactic at Texas Children’s Cancer Center. “In our lab, I feel that my biggest contribution is mentoring the next generation of researchers to think outside the box,” Taylor says. “By building a cohesive team, encouraging open collaboration, excellence and creativity, we are getting closer to a day when these diseases will be in the textbooks, not in kids.”