New Pediatric Research Highlights for Medulloblastoma Treatment

Medulloblastoma: MedulloblastomaA team led by researchers at the Baylor College of Medicine has traced the origins of an aggressive pediatric brain tumor to a malignant nest of stem-like cells in the developing brain (Cell 2024; https://doi.org/10.1016/j.cell.2024.06.011). In preclinical studies, the researchers were able to target and eliminate these immature cells, leading to tumor shrinkage in Group 3 medulloblastoma (Gr3-MB), one of four subtypes of the disease. Though more research is needed, the results suggest a potential novel way to treat children with this form of medulloblastoma. “Oncogenic phenotypes in pediatric cancers are frequently retained embryonic phenotypes rather than acquired,” said Abhirami Visvanathan, PhD, a postdoctoral fellow at Baylor and study lead author. “Targeting a small stem cell population was good enough to bring down the growth of the entire cancer.” Michael D. Taylor, Professor of Pediatrics, Hematology-Oncology, and Neurosurgery at Baylor and Texas Children's Hospital, and the study's corresponding author, added, “We believe that, as Gr3-MD develops, it retains characteristics present in embryonic development, resulting in rapid tumor growth. Our goal was to identify embryonic cells that would give rise to tumors, as well as their location and factors that drive their growth.” Also participating in the study were researchers from the Hospital for Sick Children in Toronto. Study Details Medulloblastoma is the most common malignant brain tumor in childhood. The disease arises in the embryonic hindbrain—the posterior part of the fetal vertebrate brain that corresponds to the cerebellum, pons, and medulla oblongata in the adult brain. Gr3-MB, one of four subtypes that also includes SHH, WNT, and group 4 (Gr4-MB), is the most aggressive form of the disease associated with frequent metastases at diagnosis and a 5-year survival rate of less than 50 percent. Until now, the cellular and molecular mechanisms that underlie the disease have been poorly understood. To close this knowledge gap, the research team sought to compare genes expressed by Gr3-MB cells from six tumors with those expressed by human fetal hindbrain cells during the first trimester of pregnancy. By staining specific markers with antibodies for stem cells, the researchers located the cancer stem-like cells for Gr3-MB in a brain region in the developing cerebellum called the rhombic lip, one of two distinct germinal zones from which cerebellar neurons arise. The cells are embedded in a structure unique to humans known as the interposed vascular plexus. When Gr3-MB tumors develop, they recreate the vascular plexus. Other types of medulloblastoma do not have this unique vascular structure. “We found a trace of a lineage of embryonic stem-like cells in Gr3-MB tumors,” Visvanathan said. “These cells express a protein called protogenin that is present only in these high-risk Gr3-MB, but absent in normal postnatal cerebellum.” Microscopic imaging revealed these primitive malignant cells are clustered in this immature blood vessel nest. “When medulloblastoma tumors were grown with endothelial cells, which are the building blocks of the vasculature, both the cells benefit from each other,” Visvanathan explained. “They create a symbiotic niche. We were excited to find a Gr3 medulloblastoma-like interposed vascular plexus was well-preserved in the early development.” Once the team revealed that protogenin-producing stem cells sustain tumor growth, the researchers hypothesized that targeting these malignant seed cells might prove to be a novel treatment option. Toward that goal, the researchers aimed at this population of stem-like cells in laboratory mice, using either a diphtheria toxin system or CAR-T cells, a promising strategy in which immune T cells are modified to attack a specific target—protogenin in this case—destroying the tumor. In this study, mice treated with the CAR-T cells showed diminished tumor burden and longer survival than controls. With no targeted therapies available to treat children with Gr3-MB, the results represent an “exciting therapeutic opportunity” that needs to be tested in clinical trials,” the researchers noted. Since prevention is better than treatment, the researchers also predict the development of postnatal screening tools in the future may be available to detect precancerous cells in the rhombic lip across large populations. Therapies used to treat the disease may then be adapted to prevent medulloblastoma from forming in the first place, they added. Visvanathan said that a lack of animal models to study and validate the human fetal cerebellar development and early transformational events are among the study's limitations. As for next steps, the researchers suggested that using CAR-T cells to target immature vasculature markers (CD34) might also represent a good therapeutic option. “Further studies are required to confirm the absence of expression in normal tissues so that it will have limited side effects,” Visvanathan noted. Warren Froelich is a contributing writer.

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