Wnt Activation in Non-Wnt Medulloblastoma Tumors Shown to Reduce Tumor Size and Improve Survival

Wnt Activation in Non-Wnt Medulloblastoma Tumors Shown to Reduce Tumor Size and Improve Survival

Researchers at McMaster University have found a way to make pediatric brain cancer respond better to treatment.

The most common type of brain cancer in children is medulloblastoma (MB), which accounts for around 20 percent of all childhood brain tumors. In the United States, between 250 and 500 children are diagnosed with MB each year.

MB has recently been categorized into four different subtypes. Group 1 MB, also known as the Wnt subtype as it is characterized by the activation of the Wnt signaling pathway, responds well to treatment and typically has excellent outcomes. Group 1 MB tumors rarely spread and they rarely prove to be fatal. The other three groups do not involve activation of the Wnt signaling pathway and are highly aggressive with metastatic spread. Even when treatment is provided, Group 1, 2, and 3 tumors are fatal in 20% to 30% of children.

The McMaster University researchers identified a molecule which can activate the Wnt signaling pathway in the Group 1, 2, and 3 MB subtypes, and by doing so, make these highly aggressive forms of MB more responsive to cancer therapies.

The Wnt signaling pathway is important in many different tissues during normal development, but previous research suggests that it is cancer-promoting; however, the researchers found that in certain contexts, it can function as a cancer inhibitor.

As part of his Ph.D. thesis, first author Branavan Manoranjan investigated the effect of activating the Wnt signaling pathway in Group 2, 3 and 4 MB tumors to see if Wnt made the tumor less aggressive, decreased the cancer stem cell fraction and self-renewal ability, and if activation of the Wnt pathway decreased the ability of the tumor to grow and metastasize.

Using genetic sequencing on individual brain tumor stem cells, Manoranjan found rare cells in Group 2, 3, and 4 cancers were Wnt active, and those cells generated smaller, more benign-looking tumors, whereas the cells that were not Wnt active generated aggressive metastatic tumors.

In a study on mice, the researchers tested a small molecule that was capable of turning on Wnt in the Group 2, 3, and 4 MB tumors and found there was a reduction in tumor growth and an improved survival rate. There is also a drug currently in use which has been found to selectively activate the Wnt signaling pathway. “Wnt activation could present an innovative targeted therapeutic strategy for treatment-resistant medulloblastoma,” said Dr. Sheila Singh, senior author for the study.

You can read more about the study in the paper – Wnt activation as a therapeutic strategy in medulloblastoma – which was recently published in the journal Nature Communications. DOI: 10.1038/s41467-020-17953-4

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