Study points to new approach for treating grade 3 medulloblastoma

  • Art
  • July 10, 2024

A team of researchers from Baylor College of Medicine, Texas Children's Hospital, the Hospital for Sick Children in Toronto and collaborating institutions has identified and localized a population of stem cells that initiates and maintains group 3 medulloblastoma (Gr3-MB) in the developing brain. Gr3-MB is one of the most aggressive forms of childhood brain cancer and is associated with metastatic spread and poor survival.

The researchers showed that eliminating the small population of stem cells present in Gr3-MB tumors led to tumor shrinkage in preclinical models. Although more research is needed, this new approach could lead to new ways to treat children with Gr3-MB. The study appeared in Cell.

“We believe that as Gr3-MB matures, it retains features present in embryonic development, resulting in rapid tumor growth,” said corresponding author Dr. Michael D. Taylor, professor of pediatrics, hematology — oncology and neurosurgery at Baylor and Texas Children's. He is also the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology at Texas Children's Cancer and Hematology Center. “Our goal was to identify embryonic cells that would give rise to tumors, as well as their location and factors that stimulate their growth.”

The researchers compared the genes expressed in Gr3-MB cells from six tumors with the genes expressed in human fetal brain cells during the first trimester of pregnancy.

“We found traces of an embryonic stem cell lineage in Gr3-MB tumors,” said first author Dr. Abhirami Visvanathan, a postdoctoral researcher in the Taylor lab. “These cells express a protein called protogenin that is only present in these high-risk Gr3-MB, but is absent in normal postnatal cerebellum.”

The researchers localized the cancer stem cells to a specific brain region in the developing cerebellum called the rhombic lip. The cells are embedded in a structure unique to humans known as the interposed vascular plexus. As Gr3-MB tumors develop, they recreate the vascular plexus. Other types of medulloblastoma do not have this unique vascular structure.

“Stem cells in the tumor live in this immature blood vessel nest. Both tumor and vascular cells talk to each other and maintain a symbiotic niche that benefits both cells,” Visvanathan said.

A new idea to treat Gr3-MB

The discovery that the tumors have a small population of protogenin-expressing stem cell-like cancer cells that sustain their growth inspired the researchers to test a new approach to treating GR3-MBs.

“Rather than attacking the entire tumor, we hypothesized that eliminating the small population of cancer stem cells that sustains the tumor would have a therapeutic effect, akin to disbanding an army by removing its leader,” Taylor said.

As predicted by hypothesis, therapies aimed at eliminating the cancer stem cells yielded effective results in animal models. “We targeted the protogenin-expressing cells that sustain tumor growth with CAR T-cell immunotherapy. CAR T-cell therapy is a promising strategy in which immune T cells are modified to attack a specific target — protogenin in this case — allowing them to kill the cancer. This exciting finding supports conducting further research to determine whether this strategy is effective in treating human Gr3-MB.”

The study also shows that targeting the vascular niche that supports tumor cell growth is another potential therapeutic option. Further studies are needed to investigate this possibility.

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